With more clinical information for trainees to master in the face of increasing time pressures, discussions about underlying physiology and the mechanisms of disease seem to have been de-emphasized during residency training. This reduced focus on pathophysiology and basic science may weaken trainees' clinical effectiveness and reduce their interest in pursuing research careers.In response, the authors helped to develop in 2006 a one-week immersive comparative physiology course for second- and third-year internal medicine residents at Beth Israel Deaconess Medical Center. The course, held at the Mount Desert Island Biological Laboratory, includes four modules (hematology, vascular physiology, secretory physiology, and salt and water homeostasis), each composed of basic science experiments using aquatic species and accompanied by clinical correlation discussions and group presentations.From 2007 to 2010, 72 residents rotated through the course. Most reported that it enhanced their understanding of the mechanisms of disease in their patients. After the course, residents reported that physiology played a more prominent role in their teaching and clinical decision making during both ward and intensive care unit rotations. They also reported being more likely than before the course to read about the pathophysiology of disease when faced with a clinical problem.Although cost-intensive and geographically unique, this model for teaching the mechanisms of disease could be applied elsewhere with the help of physician-scientists and clinician-educators. In this article, the authors describe the development of the course, share preliminary data evaluating progress toward its goals, and discuss future directions and lessons learned.