Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both “driver” and “passenger” genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen‐activated protein kinase kinase (MEK) inhibitors, the clinical implications of most other mutations are less often discussed and understood. In this review, we provide an overview of the high‐frequency genomic alterations and their prognostic and therapeutic relevance in melanoma. Melanoma is a highly mutated malignancy, and can produce a challenging amount of genomic data for practitioners. Herein, the authors review the clinical significance of various high‐frequency mutations and their interplay with novel targeted and immune therapies.