Born near Sun Prairie, Wisconsin, O'Keeffe received art training at the Art Institute of Chicago in 1905, the Art Students League of New York from 1907 to 1908, the University of Virgina in 1912, and Columbia University's Teachers College in New York from 1914 to 1916. She became an art teacher and taught in various schools from Texas to Virgina, and during one such position, she produced a remarkable series of charcoal drawings that led her art — and her career — in a new direction. These works orchestrated line, shape and tone, into abstract compositions. It was through these drawings that O'Keeffe caught the attention of the prominent photographer and gallery owner Alfred Stieglitz. Stieglitz exhibited her drawings at his 291 gallery, where the works of avant grade European and American artists, as well as photographers, were introduced to the American public. 

O'Keeffe arrived in New York in June 1918, to begin a career as an artist. Stieglitz vigorously promoted her work in twenty two solo exhibitions and numerous group exhibitions. As a new member of the Stieglitz circle, she associated with some of America's most distinguished early modernists — painters like Arthur Dove, John Marin, Marsden Hartley, and photographers like Paul Strand, as well as influential art critics and writers. During the 1920s, O'Keeffe painted a series of architectural pictures that dramatically depict the soaring skyscrapers and aerial views of New York City, though she was most often painting landscapes and botanical studies. In 1924 O'Keeffe began painting her close-ups of flowers, bringing the viewer right into the picture. Such daring compositions helped establish O'Keeffe's reputations as an innovative modernist. 

O'Keeffe made her first trip to New Mexico in 1929. It was a visit that had a large impact on her life, and an immediate effect on her artwork. Over the next twenty years, O'Keeffe made annual trips to New Mexico, painting in solitude, and would return to New York to exhibit her work at Stieglitz's gallery. This continued until O'Keeffe moved to New Mexico permanently in 1949. In New Mexico, there were new subjects to paint: sun-bleached animal bones and rugged mountains. Two of her most celebrated Southwestern paintings, Cow's Skull: Red, White and Blue, and Cows Skull with Calico Roses from 1931, reproduce a skulls weathered surface and jagged edges. Rather than signifying death, O'Keeffe said that the cones symbolized the eternal beauty of the desert. Later, she painted fanciful canvases that combined skeletal objects and landscape imagery in the same composition. The results were provocative and the odd discrepancies in size and scale led some to call these works surreal. Although O'Keeffe had been transfixed on the desert bones of New Mexico, it was the regions majestic landscape with its light and vivid colors that O'Keeffe would focus on for more than four decades. Often she painted the rocks, cliffs and mountains in dramatic close-up, one of her favorite settings being a site she nicknamed "Black Place." 

From the 1950s to 1970s, O'Keeffe traveled widely around the world, making trips to the Far East, South Asia, and Europe where flying airplanes inspired her last two major series. In both series, and in much of her later work, O'Keeffe increased the size of her canvases, sometimes to mural proportions, reflecting perhaps her newly expanded view of the world. O'Keeffe's rich legacy of some 900 paintings has continued to attract generations of artist and art lovers who drive inspiration from these very American images.