In 1853, a government survey party mapped Palm Springs and its natural hot springs mineral pool and established the first wagon route through the San Gorgonio Pass. In 1877, the US government gave Southern Pacific Railroad title to the odd-numbered parcels of land for 10 miles on either side of the tracks running through the Southern California desert around Palm Springs. In 1884, Judge John McCallum arrived in Palm Springs with his family, seeking health for his tubercular son. The first permanent non-Indian settler, McCallum purchased land from Southern Pacific and, with the assistance of local Indians, built a 19 mile stone-lined ditch from the Whitewater River into Palm Springs bringing in pure, precious water for irrigation.

After California became a state in 1850, various stage routes crossed the desert, and a freight line began to stop at what was called "Agua Caliente." The place was known by that name or variations of "Palm Valley" until 1890, when Harry McCallum referred in a letter to his post office address in "Palm Springs." Dr. Wellwood Murray, opened Palm Springs' first hotel, called the Palm Springs Hotel, which was located directly across the road from the Indian bathhouse where his guests could take advantage of its warm, curative waters. In 1909, Dr. Harry and Nellie Coffman started a sanitorium, The Desert Inn, which served those afflicted with tuberculosis. The Inn later became a world-renowned resort hotel catering to the very wealthy.

During World War II, the desert became the training grounds for General George S. Patton's troops as they prepared to invade North Africa. The El Mirador Hotel served as a hospital, treating wounded U.S. soldiers. Italian prisoners of war, housed at the adjoining detention camp, worked at the hospital. The airfield, built to handle military cargo and personnel planes, would become Palm Springs Regional Airport. Once a small landing field, the airport welcomes the 21st century as Palm Springs International Airport with flights nationwide and to Canada.