Native American populations decreased substantially between 1492 and 1900. But the causes, timing, and magnitude of this decline remain the source of enduring debates. This chapter outlines the contours of these debates, summarizing the history of major arguments, landmark scholarship, and recent advances in the field. During the latter twentieth century, anthropologists and historians engaged in a decades-long dispute over the absolute population of the pre-Columbian Americas dominated by documentary and ethnohistorical evidence that cleaved the field into two opposed camps. In the twenty-first century, archaeology has offered new evidence to address, if not resolve, some of these enduring questions. With the answers supplied by archaeology come new debates, with two new emerging camps: one favoring biological, geographical, and evolutionary explanations for Indigenous population decline, and the other pointing to historical contingency, settler colonial policies, and human agency. A case study of depopulation among the Pueblos of the American Southwest illustrates how these debates are playing out today.