Chemokine receptors have been documented to exert critical functions in melanoma progression. However, current drugs targeting these receptors have limited efficacy in clinical applications, suggesting the urgency to further explore the roles of chemokine receptors in melanoma. Here we found that C-X-C chemokine receptor 7 (CXCR7) was the most highly expressed chemokine receptor in murine melanoma cell lines. In addition, the expression level of CXCR7 was positively correlated with melanoma progression in the clinical samples. High CXCR7 expression was associated with shorter overall survival in melanoma patients. Increased expression of CXCR7 augmented melanoma proliferation in vitro and tumor growth in vivo, whereas knockout of CXCR7 exhibited significant inhibitory effects. Moreover, our data elucidated that CXCR7 activated Src kinase phosphorylation in a β-arrestin2-dependent manner. The administration of the Src kinase inhibitor PP1 or siRNA specific for β-arrestin2 abolished CXCR7-promoted cell proliferation. Importantly, CXCR7 also regulated melanoma angiogenesis and the secretion of vascular endothelial growth factor (VEGF). Subsequent investigations revealed a novel event that the activation of the CXCR7-Src axis stimulated the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) to accelerate the translation of hypoxia-inducible factor 1α (HIF-1α), which enhanced the secretion of VEGF from melanoma cells. Collectively, our results illuminate the crucial roles of CXCR7 in melanoma tumorigenesis, and indicate the potential of targeting CXCR7 as new therapeutic strategies for melanoma treatment.