Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Angiogenesis, primarily mediated through vascular endothelial growth factor (VEGF), is one of the key steps in tumor growth and metastasis. VEGF is now a validated target for NSCLC based on the results of the Eastern Cooperative Oncology Group trial E4599 which showed that the addition of bevacizumab, a VEGF monoclonal antibody, to cytotoxic chemotherapy improves survival compared with chemotherapy alone in patients with metastatic NSCLC. As NSCLC has complex and integrated signaling pathways, a rational approach is to target more than one of these pathways concurrently. Sorafenib, which is approved for the treatment of renal cell carcinoma, is a multitargeted signal transduction inhibitor that inhibits raf-kinases, VEGF receptor-2, platelet derived growth factor receptor-B, and c-kit. In a phase II monotherapy trial in patients with previously treated NSCLC, sorafenib demonstrated activity with a disease control rate and survival rate comparable to other small molecules. Additionally, sorafenib has shown preliminary activity in combination with chemotherapy and with epidermal growth factor receptor inhibitors. Future directions will include the development of rational combinations either with cytotoxic compounds or biologically targeted compounds and the identification of subsets of patients that might benefit from the other targets of sorafenib.