BACKGROUND: The determination that an exposure is a human teratogen is a complex process involving the application of the principles of teratology, epidemiology, biology, and clinical medicine. Shepard suggested that the “rare exposure/rare defect” or “case report method”, the astute clinician model, was one approach for establishing teratogenicity. The purpose of this article is to review selected exposures with the goal of identifying principles that lead to a working proposal for the application of this approach. METHODS: We selected three known exposures — penicillamine, fluconazole and mycophenolate mofetil — for detailed review. These agents were chosen because their evidence for causation arises mostly from clinical observations in the context of biologic plausibility. RESULTS: All three agents were originally detected based on astute observations by clinicians reporting on individual cases of a distinctive pattern of malformation or, in the case of penicillamine distinctive phenotype, after the rare exposure. All three have varying degrees of biologic evidence that support the hypothesis that each represents a human teratogen. All three meet Shepard's criteria for “proof.” CONCLUSIONS: The basic premise of this approach depends on the rarity of both the exposure and the outcome. We propose guidelines for utilization of this approach in the determination of human teratogenicity. Birth Defects Research (Part A), 2009. © 2008 Wiley-Liss, Inc.