Non-small cell lung cancer (NSCLC) is traditionally classified histologically, but until recently, the histologic subtype has had little impact on the selection of therapy. Drugs such as pemetrexed and bevacizumab are indicated for specific NSCLC subtypes, and this type of stratification represents the first step toward individualizing therapy in NSCLC. Beyond histologic features, the status of molecular targets, such as the epidermal growth factor receptor (EGFR) gene, has been shown to correlate with response to treatment with EGFR tyrosine kinase inhibitors in patients with relapsed or refractory disease and in the first-line therapy setting. New therapies targeting the EGFR and other molecular aberrations are under way to help define specific subsets of patients responsive to certain molecularly targeted treatments. The role of pathologists in guiding treatment decisions will increase because molecular profiling, together with pathologic and histologic analysis, represents the future of personalizing medicine for patients with NSCLC.