Research ethics boards (REBs) are charged with applying ethical standards to protect the rights and interests of research subjects. Little, however, is known about how REB members perceive probable impacts of research participation for subjects. Drawing on in-depth interviews with 40 Canadian REB members, we identify three frequently reported epistemic strategies, including reliance on a local REB culture or ethos, use of resident authorities, and protective imagination. Far less commonly described strategies included direct or indirect contact with research subjects. REB members also reflected upon significant gaps in their knowledge and thus the importance of knowing what we don't know. Recommendations arising from this support an evidence-based practice for ethics review involving clear epistemic standards for REBs learning about subjects' experiences.