Centuries ago, Paquimé in the Casas Grandes Valley in Mexico was a Mesoamerican trading outpost there were extensive irrigation systems, a ceremonial complex, and large amounts of trade goods. During their colonial intrusions, Spaniards encountered a disparate array of peoples whose disaggregation apparently increased during the sixteenth century. This chapter outlines several patterns of Spanish infiltration and indigenous responses of the native Indian groups of North Western Mexico in the form of first-generation rebellions and the later revolts to the European contact and Spanish rule. The natives discussed are Mayos, Yaquis, Seris, Pimas, Guarijíos, Rarámuri, and Tepehuanes. The chapter elucidates the impact of many factors conditioning cross-cultural contact in the region including the demographic shifts, the availability and accessibility of labor and natural resources valuable to the dominant society, and the intensity of extractive pressures and assaults on communal autonomy.