CXCR7, a recently identified chemokine receptor, has been implicated in directing cancer metastasis. In the present study, the potential roles of CXCR7 in the growth and metastasis of hepatocellular carcinoma (HCC) were evaluated. A chemokine receptor gene chip was used to compare the expression of CXCR7 in HCC cell lines with different metastatic potential. Effects of targeting CXCR7 by RNA interference (RNAi) on the proliferation and metastasis of HCCLM3 cells were observed in vitro and in vivo. CXCR7 expression in 116 specimens from patients with or without metastatic HCC was assessed by tissue microarray. As a result, the gene chip showed that expression of CXCR7 was significantly higher in the highly metastatic HCCLM3 cells, which was confirmed by real-time RT-PCR and Western blotting. Chemotaxis assays showed that HCCLM3 cells responded to SDF-1α from 1 to 100 μg/l and lung extractions (1 g/l). Furthermore, down-regulation of CXCR7 in HCCLM3 cells by RNAi inhibited the proliferation and invasion of tumor cells in vitro. Moreover, CXCR7 knockdown significantly reduced the activity of matrix metalloproteinase-2 and matrix metalloproteinase-9. RNAi of CXCR7 in the HCCLM3 cells also decreased the growth of tumors and the number of lung metastases in nude mice. The tissue microarray showed that HCCs with high expression of CXCR7 were prone to metastasize to the lung. These findings suggest that CXCR7 plays critical roles in the growth and metastasis of HCC. RNAi of CXCR7 inhibits the growth and invasion of tumor cells, which indicates that CXCR7 may be a potential molecular target for use in HCC therapy.