Epidermal Langerhans cells (LCs), a distinct skin-resident dendritic cell population, acquire antigen in the skin and migrate to draining lymph nodes where they are thought to initiate adaptive immune responses. To examine the functional requirement of LCs in skin immunity, we generated BAC transgenic mice in which the regulatory elements from human Langerin were used to drive expression of diphtheria toxin. The resulting mice have a constitutive and durable absence of epidermal LCs but are otherwise intact. Unexpectedly, we found that contact hypersensitivity (CHS) was amplified rather than abrogated in the absence of LCs. Moreover, we showed that LCs act during the priming and not the effector phase. Thus, LCs not only were dispensable for CHS, but they served to regulate the response, a previously unappreciated function.