Conducting clinical trials to prevent and treat infectious diseases in pregnancy is essential to saving maternal and newborn lives, though it is fraught with challenges. We have been conducting research in malaria treatment and prevention in children and pregnant women in Blantyre, Malawi for over a decade. Here, we review some of the unique challenges that we have faced in leading research studies that with rigor and integrity and maintaining the highest ethical standard. We conclude with concrete strategies to overcome some of the apparent obstacles that frequently focus on building trust through bidirectional communication with local health workers and communities. We also highlight the key role of local and international investigators to advocate for the health of the communities in which they work.