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Melson was born in Bonham, Fannin County, Texas. He was reared on a farm until he was sixteen. He attended high school in Gore, Oklahoma, and in Chicago, Illinois, before he returned to Texas to study at the two-year Odessa College in Odessa, the seat of Ector County. He studied and played music as a teenager and fronted a rockabilly band called the Cavaliers.
Beginning in 1957, first at his home in Midland, Texas, and then in Nashville, Tennessee, Melson teamed up with a virtual unknown Roy Orbison, with whom he would write a string of hits for Monument Records. Prior to their collaboration, Orbison had been solely a rockabilly performer. Although Melson himself was rooted in that music genre, he had begun writing rhythm and blues songs. Melson recognized the potential in Orbison's voice, encouraging the singer to explore its power through their first collaboration, "Only the Lonely." What resulted on March 25, 1960, was the first operatic rock ballad in the history of popular music. The song went to No. 2 on the Billboard Hot 100 chart in the United States and to #1 in the UK Singles Chart, which launched Orbison to international musical stardom. Not only did that song influence Orbison to write such operatic ballads as "In Dreams," but a few months later it also induced Orbison's friend Elvis Presley to record "It's Now or Never," based on the Neapolitan art song "'O Sole Mio."
Between 1960 and 1963, Melson recorded several singles of his own (the best known being "Hey Mister Cupid") for Hickory Records and also through Acuff-Rose Music wrote songs for some of that label's other artists including Dan Folger. He then recorded a few songs for the EMP Records label in 1964 and 1965 that achieved limited success. His last hit collaboration with Orbison came in 1963 with the writing of "Blue Bayou," although some of their cooperative efforts would be recorded in later years. The two got together again between 1971 and 1975, but while the venture did not yield the commercial success their collaboration once had, it brought such memorable songs as "Harlem Woman".
Over the years, Melson continued to perform at rockabilly and nostalgia festivals, and in 2002 he was inducted into the International Rock-A-Billy Hall of Fame in Jackson, Tennessee.