Chemokines, a group of small chemotactic cytokines, and their G-protein-coupled receptors were originally identified for their ability to mediate various pro- and anti-inflammatory responses. Beyond the influence of chemokines and their cognate receptors in several inflammatory diseases, several malignancies have been shown to be dependent of chemokines for progression, tumor growth, cellular migration and invasion, and angiogenesis; those later facilitating the development of distant metastases. In hepatocellular carcinoma (HCC), chemokines were shown to affect leukocyte recruitment, neovascularization and tumor progression. CXCL12 (stromal-derived factor 1 alpha- SDF-1) is the primary ligand for the seven transmembrane G-protein coupled receptor CXCR4. The CXCR4/CXCL12 axis exerts a variety of functions at different steps of HCC tumor progression, using autocrine and/or paracrine mechanisms to sustain tumor cell growth, to induce angiogenesis and to facilitate tumor escape through evasion of immune surveillance. In this review, we have comprehensively described the role of CXCR4/CXCL12 in HCC and also investigated the role of CXCR7, an alternative receptors that also binds CXCL12 with potentially distinct downstream effects. Preclinical data converge to demonstrate that inhibition of the CXCR4/CXCL12 axis may lead to direct inhibition of tumor migration, invasion, and metastases. This pathway is under investigation to identify potential novel treatments in HCC and other cancers. However, one of the major challenges faced in this emerging field targeting the CXCR4/CXCL12 signaling pathway, is the translation of current knowledge into the design and development of effective inhibitors of CXCR4 and/or CXCL12 for cancer therapy.