ELR+ CXC chemokines are potent promoters of angiogenesis and have been demonstrated to induce a significant portion of non-small cell lung cancer (NSCLC)-derived angiogenic activity, and support tumorigenesis in models of human NSCLC growth and metastasis in SCID mice. ELR+ CXC chemokines share a common chemokine receptor, CXCR2, which promotes the angiogenic activity of these chemokines. We hypothesized that CXCR2 in vivo mediates the proangiogenic effects of ELR+ CXC chemokines during tumorigenesis. To test this postulate, we employed a syngeneic murine Lewis lung cancer (LLC) [3LL, H-2b] heterotopic and orthotopic tumor model systems in C57BL/6 mice replete (CXCR2 +/+) and deficient in CXCR2 (CXCR2 −/−). We first determined that there was a correlation of the expression of endogenous ELR+ CXC chemokines that paralleled tumor growth and metastatic potential of LLC tumors in CXCR2 +/+ mice. Next, we found that LLC primary tumors were significantly reduced in size in CXCR2 −/− mice at 4 weeks. Moreover, we found a marked reduction in the spontaneous metastases of heterotopic tumors to the lungs of CXCR2 −/− mice. Morphometric analysis of the primary tumors in CXCR2 −/− mice demonstrated increased areas of necrosis and reduced vascular density, as compared to tumor grown in CXCR2 +/+ mice. These findings were further confirmed in CXCR2 +/+ mice in the presence of specific neutralizing antibodies to CXCR2. The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR+ CXC chemokines in a preclinical model of lung cancer, and highlights the importance of developing strategies to attenuate CXCR2 biology in NSCLC.