UV radiation (UVR)-induced skin cancers in mice are highly antigenic and rejected by the host immune system when transplanted to syngeneic recipients. Exposure to UVB radiation causes immunologic changes that inhibit the host immune system from recognizing the tumor and leads to immunologic tolerance. This tolerance involves the appearance of regulatory T cells within the tumor-bearing hosts, which inhibit immunologic recognition of the tumor. Experiments performed with chemical haptens as surrogates for tumor antigens indicate that this comes about because of abnormal antigen presentation. Antigen-presenting cells (APCs) are prevented from performing their normal function by cytokines, most notably interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha), released by keratinocytes and mast cells. Release of cytokines results from a cascade of UVR-induced events involving neuropeptides. Other immunosuppressive mediators released in the skin, as well as direct damage to Langerhans cells (LCs), are suspected of playing a role in UVR-induced immunosuppression. As a whole, data suggest a role for the immunologic effects of UVR in the pathogenesis of skin cancer.