Georgia O'Keeffe was born on a farm near Sun Prairie, Wisconsin. Between 1905 and 1916 she studied art at the Art Institute of Chicago, Art Students League of New York, University of Virginia, and Teachers College of Columbia University. Her intention was to become an art teacher, and between 1908 and 1917 she taught studio classes at schools in Virginia, Texas, and South Carolina. In 1916, O'Keeffe's drawings first came to the attention of Alfred Stieglitz (the important photographer and influential promoter of modern art), whom she married in 1924. Until his death in 1946, he regularly exhibited O'Keeffe's paintings and drawings at his New York galleries, which helped establish her reputation as a leading American artist.

For more than seventy years O'Keeffe painted prolifically, and almost exclusively, images from nature distilled to their essential colors, shapes, and designs. Prior to 1929 she derived her subjects from her life in New York City (buildings and city views) and from long summers in the country at Lake George, in upstate New York (flowers and landscapes). After 1929, when she made the first of many extended trips to New Mexico, her interest shifted to objects and scenery that characterized the American Southwest (bones and mountains). In 1949 the artist moved to New Mexico, where she resided until her death at age ninety-eight in 1986.

"Red, White, and Blue," one of O'Keeffe's most famous works, is among her earliest studies of a single animal bone isolated from its natural environment. Despite its Southwestern subject matter, the painting was most likely done in Lake George during fall 1931. The cow's skull was one of several bones O'Keeffe had shipped East the year before, with the intention of painting them. The interesting shapes and textures of the bones and their natural play of positive form and negative space repeatedly inspired her to depict them. She saw in their jagged edges, worn surfaces, and pale color the essence of the desert - a beauty that was enduring and untouchable.

O'Keeffe was able to create compositions of extraordinary simplicity that can be appreciated on many levels. "Red, White, and Blue" is masterful, both as an eloquent abstraction of form and line and as a richly symbolic image that raises issues of nationalism and religion. The compositional arrangement is starkly simple. The skull, precisely modeled and strictly frontal in its placement, becomes an image of great mystical power, like a sacred relic. The religious connotation is reinforced by the cross configuration of the extended horns and vertical support (probably the tree or easel upon which the skull was hung). Only a few years before, O'Keeffe had produced a number of dramatic depictions of the actual wooden crosses found in the New Mexico landscape.

In the 1930s, when this painting was executed, artists, musicians, and writers were interested in developing an indigenous American art form. It was an idea strongly supported by Stieglitz and his circle of artists, who sought to develop an American style of painting, rather than depictions of American subjects as produced by the Regionalists and the Social Realists. "Red, White, and Blue" is symbolic of America as O'Keeffe saw it, represented by the New Mexico desert and its relics; and almost as a joke, she painted the canvas with the three colors of the American flag.