Skin cancer is the most common human cancer, and is currently considered a global epidemic. Recently, there has been a growing interest in immunomodulators, or up-regulators of the immune response, for the treatment and cure of various forms of skin cancer, including melanoma and nonmelanoma skin cancers, cutaneous T-cell lymphoma, Kaposi's sarcoma, cutaneous extramammary Paget's disease, and vulvar intraepithelial carcinoma neoplasia. Strategies to augment the host's immune response against cancer cells and/or cancer cell antigenicity have been investigated, including recombinant cytokines, immunomodulators, dendritic cell immunization, tumor antigen vaccination, T-cell-based immunotherapy, and gene therapy. Although the current standard of care for most of these cancers includes Mohs micrographic surgery, curettage, and cryo-, laser-, or radiotherapy, immunomodulators are becoming essential in the treatment of patients who are poor surgical candidates and/or require noninvasive therapy.