Historical accounts detail numerous uses for poison ivy, poison oak, and other American Toxicodendron spp. (Anacardiaceae), despite their toxicity. The veracity of these accounts has recently been called into question by several sources. In this investigation, a multidisciplinary, hypothesis-driven approach was used to critically evaluate the veracity of such accounts by employing field studies, laboratory experiments, and literature review. Accounts regarding uses in textile production or religious rites were found to be more feasible to evaluate than those pertaining to cooking or medicine. Findings from this study suggest a new interpretation of such accounts and provide novel information regarding both the biology and ethnobotany of these plants.