The psychology of science has typically focused on the psychology of the scientist or experimenter.A neglected perspective has been the psychology of the participant in scientific research. Social science and biomedical researchers face a number of challenges when working with human participants, such as selective enrollment, aversion to random assignment, differential attrition, and low engagement.These challenges, rooted in the psychology of research participants, are not simply logistical problems but threaten the integrity of the otherwise rigorous methodology that ensures the internal and external validity of research. Such threats, unfortunately, have not been systematically examined. This review considers predominantly serendipitously documented evidence that such problems arise in typical research practice and discusses potential remedies. The review focuses upon challenges related to participant recruitment, reactivity, and retention in research. Deliberate, systematic investigation of the ways in which psychological factors interact with research methodology could help inform empirically based measures to ensure the validity of research with human participants. Social and behavioral scientists' expertise in psychological theory related to individuals' perceptions, attitudes, and behavior could very fruitfully contribute to this effort.