Simple SummaryImmune checkpoint inhibitors and BRAF/MEK inhibitors are the cornerstone of treatment for melanoma; however, primary and acquired resistance to these therapies highlight an ongoing, unmet need to develop novel treatment modalities. The emergence of monoclonal antibodies and small molecules as therapeutic platforms permits the targeting of specific mediators that drive the cancer phenotype. Melanoma represents a disease in which several driver mutations have been discovered, yet only a few effective targeted therapies exist. The effective targeting of these molecules may be the key to unlocking several potential novel therapies. Here we review the persisting efforts to identify and exploit molecular targets to optimize clinical outcomes for patients with melanoma.AbstractIt was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting theBRAFV600mutations found in 40–50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited toBRAFV600melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAFV600melanoma.