Melanoma incidence is increasing faster than any other cancer worldwide.1 Early detection is often curative, but metastatic melanoma is lethal (5-year survival <20%) due to the development of resistance to all approved drugs.1 However, emerging evidence suggests that differences in melanoma metabolism relative to non-malignant cells may provide a target to improve treatment.2-14 Specifically, melanoma cells have increased mitochondrial electron transport chain (ETC) activity, elevated levels of reactive oxygen species, and a simultaneous hyperpolarized mitochondrial membrane potential relative to non-malignant cells.4, 8, 11, 15-17 Furthermore, melanoma cells have upregulated glucose consumption and concurrent increased levels of glucose transporters (GLUTs) relative to non-malignant cells; the products of glycolysis (pyruvate and NADPH) aid in the detoxification reactive oxygen species (ROS), while the intermediates are utilized in energy production via increased oxidative metabolism.15, 18 Collectively, melanoma cells exhibit alterations in metabolic, mitochondrial, and cell-surface targets that can be potentially exploited for therapeutic strategies for selective cancer cell killing relative to non-malignant cells. The research presented here demonstrates the therapeutic potential for a new class of mitochondrial-targeted fluorescent lipophilic-cations: pyridinium derivatives (UIRF 17023.186PV1 U.S. Provisional Patent Application No. 62/268,980 Patent Pending). Importantly, the pyridinium derivatives presented in this study have not been previously investigated as a mitochondrial-targeted therapy.19-21 Furthermore, the research presented outlines the feasibility of improving melanoma cellular accumulation of these pyridinium derivatives by including a GLUT targeting moiety in the form of a hexosamine. The addition of a hexosamine molecule to pyridinium derivatives has the potential to increase melanoma cell accumulation by targeting upregulation of GLUT expression in melanoma cells relative to normal cells. Thus, the results of this study identified: (1) a triphenylvinylpyridine (TPVP) lipophilic cation derivative that increased melanoma oxidative metabolism and decreased melanoma cell viability; and (2) the targeting potential for GLUT-mediated melanoma cell specific delivery of glucosamine-modified TPVP derivatives. These findings support the hypothesis that TPVP-based therapies can be developed to exploit fundamental differences in glucose and mitochondrial metabolism to selectively kill melanoma cells relative to non-malignant cells.