Maternal mortality is an important public health and human rights problem and reflects the effects of social determinants on women's health. Understanding the extent and causes of maternal death has been insufficient to achieve the Millennium Development Goals. This article proposes a model for a comprehensive approach to maternal mortality, covering seven areas: prioritization and definition of the problem, contextual description, methodological scope, knowledge management, innovation, implementation, and a monitoring and evaluation system. This model helps address problems associated with maternal mortality and severe maternal morbidity through early monitoring of potentially fatal complications in the reproductive process. Knowledge management is important for the reorientation of policies, programs, and health care. Interaction and synergies among people, communities, and actors in the health system should be strengthened in order to improve the results of health programs. More validated scientific information is needed on how actions should be implemented in different environments. It is essential to strengthen communication among research centers, cooperation agencies, and government organizations and to include them in programs and in the definition of a new women's health agenda in the Region of the Americas.