Drugs directed against Epidermal Growth Factor Receptor (EGFR), namely tyrosine kinase inhibitors erlotinib and gefitinib, and anti-angiogenic agents, namely the anti-Vascular Endothelial Growth Factor (VEGF) antibody bevacizumab, have independently demonstrated clinical benefit in the treatment of patients with advanced non-small cell lung cancer (NSCLC), and are currently approved for use in clinical practice. Pre-clinical studies have shown promising results with the combination of anti-EGFR and anti-angiogenesis drugs in different tumor models, including NSCLC. Several clinical trials have been conducted to verify if the combination of the two therapeutic strategies could improve the outcome in the setting of advanced NSCLC. The largest body of evidence has been produced testing the combination of erlotinib plus bevacizumab, or erlotinib plus a multi-targeted receptor tyrosine kinase inhibitor, namely sunitinib or sorafenib. Furthermore, several dual inhibitors, targeting both EGFR and VEGFR, have been tested in advanced NSCLC, with the greatest body of evidence produced with vandetanib. However, despite an intriguing pre-clinical background, the combination strategy has not yet produced clinically relevant results. Several phase III trials showed an improvement in progression-free survival, underlining some activity of targeting both pathways concurrently, but no trial has demonstrated an impact on overall survival to date. Unfortunately, the vast majority of trials conducted in this setting have been performed without any selection criteria based on molecular characteristics, compromising the chance of detecting a potentially relevant benefit in selected subgroup of patients. In recent years, the important interaction between the efficacy of EGFR inhibitors and the presence of EGFR activating mutations in tumor cells has been repeatedly demonstrated. On the other hand, we still have no clear idea about predictive factors of efficacy for bevacizumab and other anti-angiogenic drugs. This is probably the real challenge to optimize the use of these drugs and to fully evaluate the real clinical potential of a combination strategy.