The highly metastatic and variable behavior of melanoma has accentuated the need for early detection and targeted therapy. Putative targets identified include those belonging to the extensive network of chemokines and their receptors. One such target is the chemokine receptor CXCR4, a G protein-coupled receptor with a 34 amino acid extracellular N-terminus, the primary ligand of which is CXCL12 (SDF-1, stromal derived factor-1). The ligand uniquely utilizes the N-terminus of CXCR4 for signal transduction and stimulates the protein kinase B (AKT)/mitogen activated protein kinase (MAPK) pathway. Functionally, the CXCR4/CXCL12 axis is believed to play a key role in cell migration and proliferation. Upregulation of CXCR4 and consequently dysregulation of the CXCR4/CXCL12 axis has been implicated in the progression of several lineage-unrelated malignancies including melanoma. The contributions of the CXCR4/CXCL12 axis in melanomagenesis are well documented. More recently, the potential cooperativity between the mutational status of BRAF and the CXCR4/CXCL12 axis has been shown, lending credence to the concept that both CXCR4 and CXCL12 may be putative targets for therapy in melanoma. In this review, we summarize the role of the CXCR4/CXCL12 axis in cancer progression and metastasis, with an emphasis on cutaneous malignancy, melanoma in particular. Furthermore, we discuss the effects of CXCL12 on CXCR4 expressing malignant cells in vitro and the potential prognostic utility of both CXCR4 and CXCL12 expressions. Lastly, we highlight the therapeutic potential of targeting this axis and the unique response of CXCR4 expression to anti-cancer treatments with an emphasis on melanoma.