Updated project metadata. Melanoma is a common type of cancer, and metastasis remains the leading cause for mortality in melanoma patients. In this study, we utilized an unbiased mass spectrometry-based quantitative proteomic method to assess, at the global proteome scale, differential protein expression in a matched pair of primary/metastatic melanoma cell lines derived from the same patient, i.e. WM-115/WM-266-4. We found that TBC1D7 is overexpressed in metastatic (WM-266-4) relative to primary (WM-115) melanoma cells. We also observed that elevated expression of TBC1D7 promotes melanoma metastasis in vitro. Bioinformatic analyses of The Cancer Genome Atlas (TCGA) data suggested that higher mRNA expression levels of TBC1D7 predict poorer survival in melanoma patients. Furthermore, we showed that TBC1D7 promotes invasion of cultured melanoma cells in vitro, at least in part, through modulating the expression levels and activities of matrix metalloproteinases 2 and 9 (MMP2 and MMP9). Together, the results from the present study support TBC1D7 as a potential driver for melanoma metastasis.