Ultraviolet (UV) radiation, particularly in the UVB region (280-320 nm), is immunosuppressive. This modulation of the immune response to antigens following UV irradiation allows the outgrowth of UV-induced skin cancers. Because UV irradiation penetrates only a few millimetres into the skin, yet can induce not only a local but also a systemic immunosuppression, the transducing mechanisms must be superficially located. Three mechanisms have been put forward, one which identifies epidermal urocanic acid as the photoreceptor, one that identifies DNA, and one that identifies cell membrane lipid peroxidation as initiating immunomodulation. While a number of mechanisms may operate (or cooperate), and do so differentially for local vs systemic suppression, considerable evidence supports urocanic acid as a key photoreceptor for immunosuppression. This review examines the immunomodulatory effects of urocanic acid, as well as its role in facilitating the outgrowth of UV-induced skin cancer.