The approach to treatment is dependent on the stage of the disease. Local and regional disease has been treated with bacillus Calmette Guérin (BCG), interleukin-2, or interferon alpha. Both the anti-tuberculosis vaccine and the two proteins are able to induce anti-tumor immune responses. However, these approaches generally have been found to have a transient effect and may exhibit significant toxicity. When possible, intralesional, rather than systemic, interleukin-2 has been used in order to avoid systemic toxicity.

Advanced melanoma can be treated using immune checkpoint inhibitors and other approaches, including kinase inhibitors and other small molecules. Inhibition of immune checkpoints reduces immunotherapy resistance, facilitating the exploitation of immunotherapy to inhibit tumor growth.

In 2015, talimogene laherparepvec was approved by the Food and Drug Administration (FDA) of the United States for the treatment of melanoma-associated cutaneous, subcutaneous or nodal lesions that are unable to remove by surgery or that are recurrent after surgical removal. Talimogene laherparepvec is effective both in monotherapy and in combination with immune checkpoint inhibitors.