Personalized targeted therapy for advanced non-small cell lung cancer (NSCLC) primarily relies on the concept of "oncogene addiction," in which multiple genetic abnormalities are addicted to one or a few genes for tumor cell maintenance and survival. Several molecular aberrations have been identified in NSCLC, with subsequent development of drugs targeted to these aberrations; gefitinib, erlotinib, and cetuximab for the treatment of NSCLC harboring epidermal growth factor receptor mutation or overexpression, and crizotinib for the treatment of NSCLC with the EML4-ALK fusion translocation oncogene being some examples. A more recent actionable target is MET, a multifaceted receptor tyrosine kinase within the human kinome. Cellular heterogeneity within an oncogene-addicted tumor can cause resistance to targeted therapy after an initial response. As our understanding of tumor heterogeneity and tumor resistance mechanisms evolves, more rational therapies and combinations of therapies can be expected.