The importance of host defense against malignant melanoma is underlined by the use of immunomodulating agents as effective therapies. Diphencyprone and 2,4-dinitrochlorobenzene (DNCB) have been used successfully as contact sensitizing agents in this regard. Through haptenation of cell surface and cytoplasmic proteins, these agents trigger a CD8(+) T-lymphocyte predominant allergic contact hypersensitivity response. Th17 cells may also play a critical role. The effectiveness of these agents at stimulating tumor defense may be limited to melanoma of the skin. Response to immunotherapy using diphencyprone and DNCB is governed by the immune status of the host, which is affected by tumor burden, UV light and age. Additionally, diphencyprone and DNCB elicit synergy with other methods of treatment and thus may be used as adjuncts. Two current prospective trials may aid in elucidating the impact that this treatment modality has on the prognosis and quality of life of patients with melanoma.