The initial peopling of the Americas has proved one of the most challenging episodes in reconstructing global prehistory, challenging because researchers struggle with the vagaries of early archaeological site preservation, and debates continue over the date and place of human entry, the rapidity and direction of dispersion, and the variety of cultural responses to climatic change during the terminal Pleistocene period. Despite many recent advances in our understanding of these issues, especially in the areas of genetics and new archaeological discoveries, the field continues facing limitations in the sampling and quality of data, the research problems defined, and the epistemologies and theories applied. Theoretical development of first American studies has been uneven, and its contribution to global issues of early human migration has been restricted. This essay discusses what is known and not known about the process of the first peopling of the Americas from the perspective of archaeology, genetics, and bioanthropology. Some approaches to fill voids in data, methods, and the broader conceptualization of the process also are considered.