Against the backdrop of the cultural history reviewed in Chap. 4, the Spanish invasion and conquest of the Central Andes in the sixteenth century represented a stunning upheaval of indigenous life. The two centuries of the Spanish Colonial Period featured violent oppression, epidemic disease, extractive economic policies, and religious imposition, but these processes were not uniform throughout the Andes. Moreover, the north coast lacked its own dedicated chronicler, making archaeological and nuanced ethnohistorical analyses all the more important for understanding the transformative effects of colonization on Lambayeque indigenous peoples. This chapter synthesizes research from the north coast and elsewhere in the Central Andes to characterize indigenous lived experiences in Lambayeque during the tumultuous early decades of the Early Colonial Period, the Toledo reforms, and political economy in the Middle/Colonial Period. Embedded throughout this discussion is a focus on the available evidence of indigenous agency and resilience in the face of demographic collapse, deplorable treatment, and attempts at cultural erasure.