Despite decades of global eradication and control efforts and explosive global economic development, malaria is the most important vector-borne disease of our day, killing more people today than 40 years ago and affecting millions worldwide, particularly poor residents of tropical regions. Global eradication efforts from the 1950s through the 1980s largely failed, leaving vector and parasite resistance in their wake. The persistence of malaria and the magnitude of its effects call for an action paradigm that links the traditional proximal arenas of intervention with malaria’s fundamental causes by addressing the environmental, economic, and political dimensions of risk. We explore the more distal determinants of malaria burden that create underlying vulnerabilities, evaluating malaria risk as a function of socioeconomic context, environmental conditions, global inequality, systems of health care provision, and research. We recommend that future action to combat malaria be directed by a broad-spectrum approach that meaningfully addresses both the proximal and fundamental causes of this disease.