Frank C. Keithley represents one of those frustrating cases in ragtime where somebody with a clear inherent musical talent suddenly disappears from view, whether from a change of fortune or attitude. He left behind only a few rags and a few clues. Frank was born in the frontier town of Madison, Iowa to farmer James Montgomery Keithley and his wife Florence Adelia French. He was the oldest of three boys including brothers Fred French (8/1/1878) and James Guy (1/7/1881). No direct relationship was found with the well-known Kentucky composer E. Clinton Keithley.

By 1880 the family had moved to Grand River, Iowa. James eventually switched occupations, leaving farming and becoming a traveling representative for the D.H. Baldwin Piano Company in the mid-1890s. This was also around the time that Frank married Harriet "Hattie" Edith West on October 13, 1898. He reappeared in 1899 in Lee, Iowa, just outside of the state capitol Des Moines, also as a state representative for Baldwin. An article in a November 1899 issue of the Iowa State Press indicates that he was visiting the firm of Price, Keith and Company, a Des Moines music store, in that capacity. In the 1900 census Frank listed himself as a musician, perhaps trying his hand at performing in addition to piano sales. For the next few years he worked as a representative of the Newman Brothers Company who dealt in pianos, and was an active member of the Iowa Music Dealer's Association.

In 1905 Frank tried his hand at composition. Since willing publishers were hard to come by that far west, he went at it himself with an associate already in manufacturing, Albert M. Carl of Newton, Iowa. They started the Keithley and Carl Publishing Company, releasing The Wise Gazebo and his first rag, Chuckles. The following year he followed it up with Lucky Lou and the rarely found song Leanna, the first of two on which he collaborated with a lyricist.

The partnership changed by 1908, and now Frank was teamed with Arthur H. Joy, also of Newton, as the Keithley-Joy Publishing Company. Under this imprint he released one of his best known works, Fluffy Ruffles, with an attractive cover that may have helped with sales. It ws based on a 1907 comic strip of the same name by Wallace Morgan, one of the earliest with a continuing story line, and she tended to dress in fluffy ruffles as well. Fluffy was a sort of liberated version of the Gibson Girl. A Broadway show of Fluffy Ruffles soon appeared, cutout dolls were often seen in Sunday supplements of the newspapers, and even two or more additional ragtime or intermezzo pieces with the same name made the rounds. Keithley's, which historians consider to be the best work with that title, was subsequently sold to the Monroe Publishing Company in Chicago which gave it a much better distribution. His follow-up work, Fuzzy-Wuzzy, also under the Keithly-Joy label, was possibly based on the Rudyard Kipling poem of the same name about British soldiers and their respect for the fuzzy-headed Beja warriers in the Sudanese, a concept not reflected on the cover. It did not fare nearly as well in popularity as Fluffy Ruffles.

The second of the two pieces that Keithley co-wrote with a lyricist was Won't You Love Me Honey from 1909 with composer Fred Heltman of Cleveland, Ohio. How the collaboration came about is unclear, given the distance that separated the two enterprising self-publishers. Two more fine rags would appear in 1910, with Vivacity Rag published by Jenkins Sons' Music in Kansas City. Many copies of that work exist today, suggesting that this beautifully illustrated piece saw fairly wide circulation. The Keithley-Joy company released a few other local vanity pieces in Des Moines, but nothing of great significance, nor widely distributed. As expected, the 1910 census taken in Des Moines showed Keithley as a music merchant, and he and Hattie had her sister Jessie West living with them.

Then it all stopped. The publishing company was liquidated, likely in the early 1910s, and Keithley would soon abandon piano sales as his line of work. There are a few mentions in Des Moines newspapers of the early-to-mid-1910s about Keithley appearing at one or another social event, playing either the piano or, more often, the "mouth harp" or harmonica, indicating another level of musical prowess. These included Lions Clubs events, as he was a member of that civic organization. His small business was sold before 1915, the same year that he was listed as a Des Moines real estate agent. Frank's 1918 draft card showed him to be a traveling salesman for Brunswick-Balke-Collender of Dubuque, Iowa, a purveyor of standard custom built billiards tables and accessories, sporting equipment, pianos, and phonographs. Within a couple of years they would produce their own line of high quality vertically-cut phonograph records, and later acquire the Vocalion Records label. In 1918, however, Frank probably handled their instruments and phonographs. In the early 1920s he was touted as a phonograph salesman for Brunswick's phonograph and record line. One of his demonstrations was detailed in the Pella [Iowa] Chronicle in their September 28, 1922 edition:

Just as the Great Depression was setting in, Keithley was listed in Des Moines in the 1930 census as the manager of an oil burning facility of some kind. It appears that he and Harriet, now 54 and 50 respectively (a bit at variance with what they actually claimed on the census record), never had children. The next clear sighting of Keithley was in the 1940 enumeration taken in Des Moines, 64-year-old Frank shown as an oil burner salesman. There was a new song registered in the 1940 Catalog of Copyright Entries, How Would You Like to Be the Girl Friend?. The premiere performance of it was reported on in the Des Moines [Iowa] Register of January 14, 1940, but the context of the emergence of this piece after 30 years of compositional silence was unclear. Keithley died in mid-1948 and is buried in Des Moines at Woodland Cemetery, along with his wife Harriet.