Bill also played with an African-American man named Arnold Schultz who, according to Bill, was a great guitarist and fiddle player. Schultz taught Bill to appreciate the blues feeling that is now in Bluegrass music. Bill started playing at age nine, and his first choice of an instrument was the guitar, but his brother Charlie and his sister Bertha played guitar, while another brother, Birch played the fiddle. Bill was assigned the mandolin in the family band, but was allowed only four strings instead of the usual eight, to avoid his making "too much noise."

While Bill was still in his teens, Charlie and Birch moved to Detroit, Michigan to seek work in the factories. They later moved to East Chicago, then to Whiting, Indiana where they found jobs in an oil refinery. Letters to Bill back in Kentucky led him to follow his brothers, and he found work in the barrel house of the Sinclair Oil Refinery. When Birch and Charlie were forced out of work during the economic depression years of the 1930s, Bill became the main support of his family. He kept his job for more than five years. During this period of time, Bill and his brothers continued to play music, usually at people's homes for dances and other gatherings. Their talents as very good dancers led them into the entertainment business in 1932. Tom Owens, who had a troupe of dancers, noticed the three brothers, their girl friends, Larry Moore and his wife at a dance. He offered the four couples jobs as dancers. They accepted and became members of the WLS radio tour out of Chicago.

Maintaining his day job along with the dancing grew very difficult, and in 1934 Bill decided he wanted to be a full time musician. Birch chose to stay on his job, so Bill and Charlie became The Monroe Brothers, and made their mark as one of the all-time great brother duets. They went to work for the Texas Crystals Company, beginning in Shenandoah, Iowa, then moving to Omaha, Nebraska. When they lost that company as a sponsor of their radio programs, they went to work for a larger company selling a similar product, The Crazy Waters Crystals Company.

During that period of time, the radio was the main form of entertainment for families, particularly in rural areas. The musicians would play a radio show in the early morning or at noon, advertising where they would make personal appearances at a school or other buildings in the listening area of their station. They had to put up posters for future shows, play the scheduled show that evening, then return for a few hours sleep, and do it all over again the next day. While this was a hard life, it was considered much better than farm or factory work, plus the gain of fame, of being a radio star, made these jobs most attractive. When the fans began to dwindle in number at the personal appearances, the area was said to be "played out," and the band would move to another radio station. The Monroe Brothers moved to Columbia, South Carolina, then to Charlotte, North Carolina, where they recorded for RCA's Bluebird Label on February 17, 1936. Charlie did all the lead singing with Bill playing background and breaks on the mandolin, then singing tenor on the choruses of the songs. Charlie's guitar work, particularly the runs, are still used by many of the rhythm guitarists in today's Bluegrass bands.

When the Monroe Brothers split at Raleigh. North Carolina in 1938, Bill went to Little Rock, Arkansas to try his own musical ideas. He formed his first band, briefly called The Blue Cross Boys, then changed the name to The Kentuckians. The Little Rock area did not prove to be productive enough, so Bill moved to Atlanta, Georgia, where he formed a new group called, Bill Monroe and his Blue Grass Boys, the band name he used throughout the remainder of his career. The instruments in the new band in addition to Bill's mandolin were guitar, fiddle and a jug. The band practiced for six weeks and then moved to Asheville, North Carolina staying three months. There Bill added a bass fiddle to the group, replacing the jug. Bill's first groups were playing the string music of those days, but Bill began to emphasize the fiddle and the blues.

The group played a variety of songs, instrumentals and gospel music, laying the groundwork for the new style. Already their sacred quartets demonstrated all the exciting hallmarks of bluegrass singing. The bass player usually did the comedy routines, a throwback to the minstrel days of the medicine shows, with another member acting as the "straight man." Bill moved once again, to Greenville, South Carolina, and at this point began to feel good about the music his band was creating.

The moving of the Blue Grass Boys from one area to another ceased when Bill took them to Nashville, Tennessee to audition for the Grand Ole Opry in October. 1939. Bill recalls, "I went in to audition and Harry Stone, Manager of the Opry and George D. Hay, The Solemn Old Judge, were going out to lunch, but they told me they would be right back. When they came back, we played some tunes for them, and they hired me right there. They told me, 'if you ever leave the Opry, you'll have to fire yourself.' Bill was a member of the Grand Ole Opry for almost fifty eight years.

Bill joined the Grand Ole Opry on October 26, 1939. He and his band quickly became one of the most popular acts on the Opry, and being a member of this cast gave them the opportunity to be heard every Saturday night throughout most of North America. Bill made the first recording with his own band at the Kimball Hotel in Atlanta, Georgia on October 7, 1940 for Victor Records. One of the songs recorded was "Muleskinner Blues," the first song Bill sang on the Grand Ole Opry, his first recorded solo, and the only time he played guitar on a recording. Clyde Moody, who usually played guitar, played mandolin, Tommy Magness played fiddle and took all the instrumental breaks and Bill Westbrook, who played the comic character, "Cousin Wilbur," on the stage shows, played bass fiddle. The late Jimmy Rodgers had written and recorded "The Muleskinner Blues" as "Blue Yodel # 8."

Bill had heard "Snuffy" Jenkins play the three finger style of banjo in the Carolinas, but he chose David Akeman, known as "The Kentucky Wonder, String Bean," who played the two-finger and clawhammer styles, as his first banjo player. Wilene Forrester, who used the name, "Sally Ann," played accordion with the Blue Grass Boys from 1942 until 1945. She was the wife of "Howdy" Forrester, who had played fiddle with Bill briefly in 1942 before entering military service. Bill hired Jim Shumate as the new fiddle player. Shumate yielded to Forrester after the war, but Howdy soon joined Roy Acuff, with whom he stayed for many years. Bill Monroe then engaged Robert R. "Chubby" Wise to play the fiddle.

The music of Bill Monroe showed many changes in the early days of it's development. These changes sometimes derived from the changing personnel or Bill's constant searching for the sound he wanted to achieve. Bill always showed great judgment in the use of members of his band., allowing them to develop their individual talents, and spending many hours instructing them in his style of music. This would usually find them leading their own band when they left the Blue Grass Boys. Bill explains: "You know, they only stay with the Blue Grass Boys for about three years, and they get to be heard on the Opry, and I call their name when they play or sing, and that's good for them. They get to be known, and they can use that when they go on to their own bands."

The musical combination of Bill Monroe, mandolin, Chubby Wise, fiddle, Lester Flatt, guitar, Earl Scruggs, banjo and Howard Watts (Cedric Rainwater) bass fiddle, have become known as the "Classic Bluegrass Band." The first recording session for this group took place on September 16, 1946 in Castle studios, Nashville, Tennessee, with eight songs waxed. The addition of Earl Scruggs' hard driving three finger style of banjo playing, to Bill's soaring tenor over Lester's lead, and the "bluesy" fiddling of Chubby Wise, all combined to produce the style copied by Bluegrass bands around the world.

Oddly, Don Reno was all set to become Bill's banjo player in 1943, but he could not accept the job as he had to enter military service. The following story was often told by Lester Flatt:
"Bill told me he had an eighteen year old boy he wanted to audition as a possible replacement for Stringbean. Now String was a great fellow, and a good friend of mine, but his timing would just drag you down on a song, so I didn't want Bill to hire another banjo player. I told Bill to tell that feller to keep his banjo in the case, but when I heard Earl Scruggs pick the banjo, that all changed."

The debate about when Bluegrass Music really began could continue infinitely. Some people believe Bluegrass started in 1934 when Bill and Charlie Monroe initiated their professional careers, while others believe Bill started it when he recorded "Muleskinner Blues" in 1940. It must be recognized, however, that when Scruggs, Flatt, Wise and Watts joined Bill's band, they created a sound that has been maintained, vocally and instrumentally, in all of Bill's bands ever since. Bill Monroe's mandolin case had the following printed on it for many years: