Mutations in SLC45A2are responsible for oculocutaneous albinism type 4 in many species and associated with melanoma susceptibility, but the molecular mechanism is unclear. Here, we used Slc45a2-deficient melanocyte and mouse models to elucidate the roles of Slc45a2 in melanogenesis and melanoma metastasis. We find that the acidified cellular environment impairs the activity of key melanogenic enzyme tyrosinase in Slc45a2-deficient melanocytes. Slc45a2 is identified as a proton/glucose exporter in melanosomes, and its ablation increases acidification of melanosomal pH through enhanced glycolysis. Intriguingly, 13C-glucose labeled metabolic flux and biochemical assays show that melanosomes are active glucose-metabolizing organelles, indicating that elevated glycolysis mainly occurs in melanosomes due to Slc45a2-deficiency. Moreover, Slc45a2-deficiency significantly up-regulates the activities of glycolytic enzymes and PI3K/Akt signaling to promote glycolysis-dependent survival and metastasis of melanoma cells. Collectively, our study reveals that the H+/glucose exporter Slc45a2 mediates melanin synthesis and melanoma metastasis primarily via modulating melanosomal glucose metabolism.