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Carcinogenesis is a complex pathological process induced by abnormalities in the genome, cell-cycle dysregulation, loss of the programmed cell death process, and upregulation of oncogenic pathways associated with proliferation, migration, and survival, among others. Despite recent advances in molecular and tumor biology in non–small-cell lung cancer (NSCLC) and the introduction of several targeted agents, the disease continues to have a dismal survival. Nonetheless, the future looks promising; conventional cytotoxic chemotherapy regimens in combination with targeted agents have shown better response rates and survival than those seen in the past. These targeted agents have the advantage of blocking or inhibiting specific pathways necessary for tumor growth, proliferation, and metastases, without significantly affecting quality of life by having an acceptable toxicity profile. Thus, these novel agents harbor a hope in the treatment of NSCLC and many other malignant diseases when they can be used either in combination with other chemotherapy drugs in several lines of treatment or as a single agent in maintenance therapy until progression of disease, or even more attractively, in combination with other targeted agents themselves. In this review, we discuss second-line treatments for patients who have NSCLC, including targeted agents and their development in this specific setting as part of our armamentarium in lung cancer.