While the role of molecular alterations has yet to be defined in the treatment of SCLC, thymoma, and mesothelioma, there is an increasing recognition that molecular alterations in NSCLC are important predictors of response to novel targeted therapies. Small molecule tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) signaling pathway, such as erlotinib and gefitinib, improve survival in the second-line treatment of unselected patients with NSCLC. However, retrospective subgroup analysis of these clinical trials has revealed that patients with particular clinical features were more likely to benefit from therapy, such as those with tumors of adenocarcinoma histology, women, Asian ethnicity, and light or never smokers. Conventional Deoxyribonucleic acid (DNA) sequencing of tumors from multiple series of patients that had dramatic responses to gefitinib, as compared with patients without responses, revealed the presence of characteristic genetic mutations in the EGFR gene.4-6 The previously identified clinical markers of response to EGFR TKIs were found to be commonly associated with the presence of these mutations; thus, these clinical features are actually believed to be surrogates for the molecular biomarker of EGFR mutation. Over 90% of EGFR tyrosine kinase domain mutations associated with sensitivity to EGFR Tyrosine kinase inhibitor (TKI) therapy fall into two categories, in-frame deletions in exon 19, and the L858R point mutation in exon 21. These mutations appear to specifically activate both cell proliferation, via activation of the MAP kinase pathway, and survival signals, via activation of the PI3 kinase pathway.7 Therefore, tumors with EGFR mutations are "oncogene addicted" to EGFR survival signals, relying exclusively upon the EGFR signaling cascade to maintain viability, which explains their exquisite sensitivity to TKI therapy. A number of recent large randomized studies have conclusively demonstrated that clinical selection of patients alone is inadequate, and instead establish EGFR mutation status as the single most important predictive marker of response to EGFR-TKI therapy.8-10 In another emerging but similar story, genetic fusion of the anaplastic lymphoma kinase (ALK) tyrosine kinase to a partner protein, EML4, appears to strongly predict sensitivity to the ALK TKI, crizotinib. 11 In addition, there is evidence that less common mutations in NSCLC, such as BRAF mutations and ERBB2 (e.g. HER2) mutations, may also predict response to targeted therapies.