Melanoma and its associated alterations in cellular pathways have been growing areas of interest in research, especially as specific biological pathways are being elucidated. Some of these alterations include changes in the mitochondrial metabolism in melanoma. Many mitochondrial metabolic changes lead to differences in the survivability of cancer cells and confer resistance to targeted therapies. While extensive work has gone into characterizing mechanisms of resistance, the role of mitochondrial adaptation as a mode of resistance is not completely understood. In this review, we wish to explore mitochondrial metabolism in melanoma and how it impacts modes of resistance. There are several genes that play a major role in melanoma mitochondrial metabolism which require a full understanding to optimally target melanoma. These include BRAF, CRAF, SOX2, MCL1, TRAP1, RHOA, SRF, SIRT3, PTEN, and AKT1. We will be discussing the role of these genes in melanoma in greater detail. An enhanced understanding of mitochondrial metabolism and these modes of resistance may result in novel combinatorial and sequential therapies that may lead to greater therapeutic benefit.