Treatment decisions for patients with lung cancer have historically been based upon tumor morphological analysis. Over the past decade, some molecular alterations have been identified as being necessary and sufficient to drive tumor carcinogenesis. These "driver" mutations occur in genes that encode signaling proteins critical for cellular proliferation and survival. Epidermal growth factor (EGF) receptor (EGFR) mutations are the best illustration of the therapeutic relevance of identifying such molecular clusters of lung cancer based on driver genetic alterations that predict the efficacy of specific tyrosine kinase inhibitors, a strategy referred to as "personalized medicine." Besides EGFR and ALK, other genes harboring driver molecular alterations have been identified as part of integrated genomic studies of lung cancers. The objectives of this review are (1) to provide the reader with preclinical and clinical data on these new oncogenic mutations, focusing on druggable ones; (2) to discuss the dynamic nature of lung cancer molecular features in the context of acquired resistance to specific inhibitors; and (3) to highlight emerging data on other cancer hallmarks that may be of interest from a therapeutic perspective in the next future. From bench to bedside, personalized medicine represents a major revolution in the treatment of lung cancer.