The purpose of this paper is to characterize the interrelationships between macropolitical, social and economic policies, human migration, agricultural development, and malaria transmission on the Amazon frontier. We focus our analysis on a recent colonization project, POLONOROESTE, in the state of Rondonia. Employing data from field surveys in 1985-1987 and 1995, we use spatial statistical methodologies linked to a geographical information system (GIS) to describe the patterns of human settlement in the area, the ecological transformations induced by forest clearance practices, and the manner in which these factors determine gradations of malaria risk. Our findings show that land use patterns, linked to social organization of the community and the structure of the physical environment, played a key role in promoting malaria transmission. In addition, the location of each occupied area is itself an important determinant of the pattern of malaria risk. Based on lessons learned from our spatial and temporal characterization of malaria risk, we propose policies for malaria mitigation in the Brazilian Amazon.