He was intrigued by the cowboys, former cattle drivers, who worked on his father's ranch, and also by the spirituals that he heard whenever a family servant brought him to the services of an African-American church.

As a young boy, he was sent by train each Saturday to San Angelo, where he took piano lessons with Charles Finger, who later became a prolific author and literary magazine editor.

It was Guion's arrangement that transformed "Home on the Range" from a little-known cowboy tune to one of the most famous and popular of all western songs, proclaimed by President Franklin D. Roosevelt as his own favorite.

Guion's ballet Shingandi, originally written for two pianos but later orchestrated by Ferde Grofé and introduced by Paul Whiteman's orchestra in November 1931 both in a live concert and in a nationwide radio broadcast, is one of the most significant American dramatic works in the style of primitivism.

That same year he received a commission from the Houston Symphony Orchestra to write the fourteen-movement Texas Suite, which contains several newly composed pieces along with orchestrations of some of his previous works.