Lung cancer is the leading cause of cancer deaths worldwide. Small cell lung cancer (SCLC), which comprises 15% of all lung cancers, is almost exclusively due to smoking and is highly aggressive due to early widespread metastasis. While combination chemotherapy has lead to modest improvements in outcome, the five-year overall survival for SCLC remains at 5%. Identifying distinct biochemical pathways of metastasis and chemotherapy resistance in SCLC may lead to novel therapeutic approaches and improve survival in SCLC patients. The chemokine receptor CXCR4 is emerging as an important target in cancer growth, metastasis, relapse and resistance to therapy. In this article, we review the structure and function of CXCR4 and its ligand, CXCL12, as well as mechanisms of CXCR4/CXCL12 signal transduction in lung cancer. We review the current preclinical and translational research involving this pathway in lung cancer and the clinical development of several novel agents targeting the CXCR4/CXCL12 pathway. Further understanding of the CXCR4/CXCL12 pathway in SCLC and NSCLC may provide a rationale for innovative research on the CXCR4 receptor as a potential novel therapeutic target in lung cancer.