Non–small cell lung cancer (NSCLC) is usually diagnosed when it is not amenable to curative surgery or radiation. Many of these patients are candidates for systemic therapy. Median survival is only approximately 10 months, and, accordingly, treatment in advanced NSCLC is evolving toward a more personalized approach with the identification of genetic abnormalities based on biomarkers. For example, gene mutations in EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) lead to a cascade of pathways resulting in uncontrolled growth, proliferation, and survival of tumor cells. Targeted therapies are aimed at the products of these mutated genes and include agents such as erlotinib and gefitinib (in EGFR-mutant NSCLC) or crizotinib (in ALK-positive NSCLC). Antiangiogenesis agents such as bevacizumab are another category of targeted therapy that inhibits vascular endothelial growth factors. The imaging characteristics of advanced NSCLC with genetic abnormalities, the evolution of targeted therapies and their imaging manifestations will be discussed.