Non-small cell lung cancer (NSCLC) is not one disease but a heterogeneous mix of multiple clinically, pathologically, and molecularly distinct entities. Following the identification of activating mutations in the EGFR that conferred sensitivity to EGFR tyrosine kinase, other promising molecular targets have been identified in patients with adenocarcinoma including rearrangements involving ALK, ROS, and RET as well as activating mutations in BRAF, Her2 and amplification of cMET. A recent phase III study has provided evidence of the superiority of the ALK TKI crizotinib in NSCLC patients with ALK rearrangements now mandating testing for both EGFR and ALK to drive therapeutic decision making in NSCLC. In squamous cell carcinoma potentially actionable genetic alterations in FGFR1, DDR2, PTEN and PIK3CA have been identified. Recent characterization of whole genomes have provided further insights into novel potentially therapeutically tractable targets. However, challenges remain in identifying small subsets of NSCLC patients with these “actionable mutations” and dealing with acquired resistance to target therapy.