Crucial steps in tumor growth and metastasis are proliferation, survival, and neovascularization. Previously, we have shown that receptors for CXCL-8, CXCR1, and CXCR2 are expressed on endothelial cells and CXCR2 has been shown to be a putative receptor for angiogenic chemokines. In this report, we examined whether tumor angiogenesis and growth of CXCL-8-expressing human melanoma cells are regulated in vivo by a host CXCR2-dependent mechanism. We generated mCXCR2(-/-), mCXCR2(+/-), and wild-type nude mice following crosses between BALB/c mice heterozygous for nude(+/-) and heterozygous for mCXCR2(+/-). We observed a significant inhibition of human melanoma tumor growth and experimental lung metastasis in mCXCR2(-/-) mice as compared with wild-type nude mice. Inhibition in tumor growth and metastasis was associated with a decrease in melanoma cell proliferation, survival, inflammatory response, and angiogenesis. Together, these studies show the importance of host CXCR2-dependent CXCL-8-mediated angiogenesis in the regulation of melanoma growth and metastasis.