Over the past few decades, there has been increasing attention focused on the ethics of health research, particularly in low- and middle-income countries. Despite the increasing focus on the literature addressing human protection, community engagement, appropriate consent procedures and ways to mitigate concerns around exploitation, there has been little discussion about how the duration of the research engagement may affect the ethical design and implementation of studies. In other words, what are the unique ethical challenges when researchers engage with host communities for longer periods (10 years or more), and what special considerations does this time commitment generate when applying ethical principles to these kinds of studies? This article begins to outline key areas of ethical concern that arise during long-term, sustained research activities with communities in low-resource settings. Through a review of the literature and consultations with experts in health systems, we identified the following key themes: fair benefits and long-term beneficence; community autonomy, consultation and consent; impacts on local health systems; economic impacts of research participation; ethical review processes; and institutional processes and oversight within research organizations. We hope that this preliminary exploration will stimulate further dialogue and help inform ethical guidance around long-term research engagements in the developing world.