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O'Keeffe was born on November 15, 1887, in a farmhouse located at 2405 Hwy T in the town of Sun Prairie, Wisconsin. Her parents, Francis Calyxtus O'Keeffe and Ida (Totto) O'Keeffe, were dairy farmers. Her father was of Irish descent. Her maternal grandfather George Victor Totto, for whom O'Keeffe was named, was a Hungarian count who came to the United States in 1848.

O'Keeffe then spent part of nearly every year working in New Mexico. She collected rocks and bones from the desert floor and made them and the distinctive architectural and landscape forms of the area subjects in her work. Known as a loner, O'Keeffe explored the land she loved often in her Ford Model A, which she purchased and learned to drive in 1929. She often talked about her fondness for Ghost Ranch and Northern New Mexico, as in 1943, when she explained: "Such a beautiful, untouched lonely feeling place, such a fine part of what I call the 'Faraway'. It is a place I have painted before ... even now I must do it again."  Due to exhaustion and poor health, she did not work from late 1932 until about the mid-1930s. She was a popular and reputed artist. She received a number of commissions and her works were exhibited in New York and other places. In 1936, she completed what would become one of her most well-known paintings, Summer Days, in 1936. It depicted a desert scene with a deer skull with vibrant wildflowers. Resembling Ram's Head with Hollyhock, it depicted the skull floating above the horizon.  In 1938, the advertising agency N. W. Ayer & Son approached O'Keeffe about creating two paintings for the Hawaiian Pineapple Company (now Dole Food Company) to use in their advertising. Other artists who produced paintings of Hawaii for the Hawaiian Pineapple Company's advertising include Lloyd Sexton, Jr., Millard Sheets, Yasuo Kuniyoshi, Isamu Noguchi, and Miguel Covarrubias. The offer came at a critical time in O'Keeffe's life: she was 51, and her career seemed to be stalling (critics were calling her focus on New Mexico limited, and branding her desert images "a kind of mass production"). She arrived in Honolulu February 8, 1939 aboard the SS Lurline, and spent nine weeks in Oahu, Maui, Kauai, and the island of Hawaii. By far the most productive and vivid period was on Maui, where she was given complete freedom to explore and paint. She painted flowers, landscapes, and traditional Hawaiian fishhooks. Back in New York, O'Keeffe completed a series of 20 sensual, verdant paintings. However, she did not paint the requested pineapple until the Hawaiian Pineapple Company sent a plant to her New York studio.  During the 1940s O'Keeffe had two one-woman retrospectives, the first at the Art Institute of Chicago (1943). Her second was in 1946, when she was the first woman artist to have a retrospective at the Museum of Modern Art (MoMA) in Manhattan. Whitney Museum of American Art began an effort to create the first catalogue of her work in the mid-1940s.  In the 1940s, O'Keeffe made an extensive series of paintings of what is called the "Black Place", about 150 miles west of her Ghost Ranch house. O'Keeffe said that the Black Place resembled "a mile of elephants with gray hills and white sand at their feet." She made paintings of the "White Place", a white rock formation located near her Abiquiu house.
Georgia O'Keeffe