Docetaxel, pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors (gefitinib and erlotinib) are recommended second-line therapy for advanced non-small cell lung cancer (NSCLC) patients with disease progression. Although erlotinib is the only recommended third-line therapy, several drugs are being used in the clinic. Recent studies have focused on combining targeted agents with approved therapies, including broad-spectrum multikinase inhibitors targeting multiple ErbB Family receptors and multitargeted anti-angiogenic agents targeting the vascular endothelial growth factor receptor, platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Here, we review targeted therapies that are being evaluated in second- and third-line settings in NSCLC, including the ErbB Family Blocker afatinib (BIBW 2992), multityrosine kinase inhibitors (pelitinib [EKB-56]), neratinib [HKI-272], canertinib [CI-1033], lapatinib [GW-572016], dacomitinib [PF-299804]) and multitargeted anti-angiogenic agents (vandetanib [ZD6474], sunitinib [SU11248], sorafenib [BAY43-9006], nintedanib [BIBF1120], axitinib [AG-013736], cediranib [AZD2171], motesanib [AMG 706], linifanib [ABT869] and pazopanib [GW786034]).