Reproductive health research in low-resource settings poses unique and complex challenges that must be addressed to ensure that global research is conducted with strict adherence to ethical principles, offers direct benefit to the research subjects, and has the potential for adoption of positive findings to the target population. This article addresses challenges to conducting reproductive health research in low-resource settings in the following areas: (1) establishment and maintenance of global collaboration, (2) community partnerships, (3) ethical issues, including informed consent and the role of incentives, (4) staff training and development, (5) data collection and management, and (6) infrastructure and logistics. Particular attention to these challenges is important to ensure that research is culturally appropriate and methodologically sound and enhances the adoption of health-promoting behaviors. Rigorous evaluation of interventions in low-resource settings may be a cost-effective and time-efficient way to identify interventions for large-scale program replication to improve women's health.