Although the O'odham were able to solve their subsistence needs with diversification, they faced a new threat to their existence when the Spanish arrived. Groups of Apaches were also sweeping down from the east, and the Spaniards enlisted the O'odham as allies against the Apaches. Despite reports that describe Jesuit contact as peaceful, the O'odham obviously objected to their presence, for they revolted against the Spanish in 1695 and again in 1751, and sporadically throughout the entire period of Spanish and Mexican domination, which lasted until 1853. By the time the king of Spain had expelled the Jesuits from the New World in 1767, they had established over 24 missions and mission-visiting stations (visitas) in O'odham territory. In 1775, one of the two presidios was moved to Tucson, where the mission visita of San Xavier del Bac was located.

San Xavier del Bac became an important influence among the Arizona Tohono O'odham, and the annual pilgrimage to Magdalena, Sonora drew Indians from a wide area through the 1800s. Still practiced today, this pilgrimage probably began in the two decades after the 1821 Mexican Revolution. This event combines the image of St. Francis Xavier, founder of the Jesuits, with the October 4 feast day of St. Francis of Assisi, the patron saint of the Franciscan order. In the early 19th century when Catholic priests withdrew from the outlying areas because of the intensification of Apache raiding, the Tohono O'odham continued to carry out Christian rituals. Without pressure to conform to the strictures of Catholicism, the Tohono O'odham, unlike the Pueblos of the Rio Grande area, had no need to compartmentalize the two religious systems. Instead of integrating their traditional beliefs and practices with the newly introduced religion as did the Yaqui, the Tohono O'odham simply added aspects of Catholicism to their own religion (Anthropologist Edward Spicer called this "simple addition."). They added the veneration of a powerful saint-St. Francis Xavier-interpreting him as a source of supernatural healing power similar to existing Tohono O'odham mythological figures. By 1900, the family who owned pictures of St. Francis conducted weekly services with fellow villagers in small chapels; services consisted of Catholic prayers and hymns in the Spanish language, all in praise of the saint. Individuals also continued to participate in the traditional religion.

The underlying theme of O'odham ceremonialism was the attainment of the power needed to sustain human society. Individual men embarked on journeys to contact powerful supernatural forces by killing an eagle, slaying an enemy, or undertaking the 8-day pilgrimage to the Gulf of California to seek the ocean wind that brings the rain. Known as the Salt Pilgrimage, this arduous, almost waterless journey was taken with other men who were required to follow taboos and to speak a special language to ensure reverence for the special powers with which they were in contact.

Also important in bringing rain was the communal wine feast held each summer. Medicine men fermented some of the syrup from the saguaro cactus fruit into ceremonial wine for the 4-day ceremony. (The saguaro cactus is so important to Tohono O'odham culture that its harvest in mid-summer marked the beginning of their traditional year.) During the two nights it took for the syrup to ferment in the village communal round house, men, women, and children danced in a large circle outside the Rain House around a fire in the middle of the ceremonial grounds. After guests from neighboring villages arrived, orations began that described the desolation of the land without rain and that the world would burn unless rain fell.

As is true of all peoples discussed in this course, the O'odham are a contemporary people. They have six reservations, two of which they share with the Maricopa, a River Yuman tribe who moved east to live near their Akimel O'odham (Pima) allies. Akimel O'odham (Pima) and Maricopa live in the Salt River Pima-Maricopa Community and the Gila River Indian Community. The O'odham of the Ak-Chin Community consider themselves to be Ak-Chin O'odham rather than Tohono O'odham or Akimel O'odham. The Tohono O'odham Nation includes the main reservation west of Tucson, Arizona and noncontiguous reservations at San Xavier and Gila Bend. In 1997, the Bureau of Land Management turned over a tiny piece of land to the Hia C-ed O'odham, and earlier, in the mid-1980s, about 1,200 Hia C-ed O'odham received recognition from the Tohono O'odham Nation, giving them equal access to social services, education, and health benefits.

Most Tohono O'odham who live on the reservation work either for the tribal government or in civil service jobs with federal agencies; over half the tribe now lives off-reservation. One solution to unemployment and underemployment is the Tohono O'odham Desert Diamond Casino, the income from which is being used to build and staff their own college, a new nursing home, a tribal scholarship that enables students to pursue higher education.