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Community and stakeholder engagement (CSE) is increasingly acknowledged as foundational to global health research. This commentary builds on the multisite framework for CSE described in an eco-health study conducted in Southern Africa. We acknowledge the context-specific nature of some of the challenges for CSE and draw attention to significant issues and concerns that arose from our studies of CSE in the context of multisite HIV prevention trials in South Africa, India, and Canada: (a) Pretrial-historically based mistrust, identification of appropriate gatekeepers, and considering the breadth of community; (b) Trial implementation-impact of early trial cessations, appropriate community roles and responsibilities, and multifaceted stigma; and (c) Posttrial-supporting and sustaining CSE mechanisms independent of particular trials. Many of these challenges are exacerbated by widespread disparities in wealth and power between trial sponsors and participating communities, further supporting the central importance of sound CSE practices and infrastructures to advance ethical biomedical and public health research.