Until recently, non–small-cell lung cancer (NSCLC) was treated as a single disease despite recognition of its histologic and molecular heterogeneity. Recent clinical trials, however, demonstrate that histology is an important factor for individualizing treatment, based on either safety or efficacy outcomes. For example, the labeling of the licensed agents bevacizumab and pemetrexed is restricted to patients with nonsquamous cell NSCLC. For bevacizumab, this restriction is due to an apparent association between squamous cell histology and severe pulmonary hemorrhage, whereas for pemetrexed, superior treatment effects have been observed in patients with nonsquamous cell histology. Given fewer agents are both active and tolerable in patients with squamous cell carcinoma compared with adenocarcinoma, and the nature of this particular phenotype of NSCLC, new drugs are needed for this histology. In this new histology-based treatment era, questions persist. Can pathology accurately distinguish the histologic subtypes of NSCLC? Can we use cytologic diagnosis? In the future, will molecular profiling of tumors trump histologic analysis? Herein we describe how therapy for NSCLC is evolving on the basis of a better understanding of molecular mechanisms underlying NSCLC histologic heterogeneity and tumorigenesis.