As a result of improved effectiveness of first-, second-line and maintenance therapeutic regimens in non-small cell lung cancer, there is need for new options as third-line treatment. Erlotinib and gefitinib are currently the only drugs of proven efficacy in the third-line setting. Chemotherapy drugs, such as pemetrexed, are being investigated, as are many new agents, such as cetuximab, sunitinib, sorafenib, everolimus, enzastaurin, afilbercept. These novel targeted therapies seem to improve response rates and progression-free survival and their toxicity is tolerable. In an effort to prolong survival while maintaining quality of life, large prospective studies are needed to examine the effectiveness and safety of third-line regimens in these patients.