Food and Drug Administration-approved treatment for metastatic melanoma, including interferon alpha and interleukin-2, offer a modest benefit. Immunotherapy, although has not enjoyed high overall response rates, is capable of providing durable responses in a subset of patients. In recent years, new molecular-targeted therapies have become available and offer promise of clinical benefit, although low durability of response. It is not yet clear how best to integrate these 2 novel modalities that target the immune response to melanoma (immune therapy) or that target molecular signaling pathways in the melanoma cells (targeted therapy). Many signal transduction pathways are important in both tumor cell and T-cell proliferation and survival, which generate risk in combining targeted therapy and immunotherapy. This review focuses on the role of targeted therapy and immunotherapy in melanoma, and discusses how to combine the 2 modalities rationally for increased duration and response.