My goal with this research is to contribute to our current understanding of how contact with and incorporation into the modern world-system may affect the trajectory of change among indigenous peoples. I do this by examining (1) the nature of social organization among the various peoples known collectively as Mississippians; (2) the processes involved in the supplanting of their political, cultural, and economic structures during the sixteenth-century conquest; (3) the changes that occurred within the precolonial Mississippian cultures following their initial contact with European agents in the late fifteenth and early sixteenth centuries; and (4) the impact of such changes on the Mississippian people’s subsequent integration into the world-system. By expanding our understanding of the process of incorporation and the concurrent structural transformations, I seek to extend Chase-Dunn and Hall’s hypothesis that episodes of incorporation, disintegration, and reincorporation may vary in highly predictable and interrelated ways in “interchiefdom systems as well as interstate systems.” In this essay I employ the methodologies of historical sociology, which are aimed at studying the past to discover how societies operate and evolve. I start from the perspective that we can best understand social change in terms of its historical specificities rather than generalizations that dominate contemporary sociology. I incorporate historical detail gleaned from previously published works from the fields of anthropology, archaeology, and history to develop a detailed explanation of what Peter Peregrine has called the “Mississippian World-System,” the nature of its sixteenth-century contacts with European agents, and the effect of those contacts on the area’s subsequent incorporation into the European world system. When did the Mississippian culture first begin to decline and under what specific conditions? How were these changes related to contact with early European explorers? The Mississippians are a fitting case on which to focus since the North American continent was largely “external” to the modern world-system prior to contact with European explorers in the decades following 1492. By focusing on this episode of incorporation and the associated transformation of the Mississippian system’s social structures and processes, I hope to understand better the dynamics of change that occur when two “worlds” collide.