Precision oncology is now the evidence-based standard of care for the management 
of many advanced non-small cell lung cancers (NSCLCs). Expert consensus has 
defined minimum requirements for routine testing and identification of epidermal 
growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or 
exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements 
(5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative 
targeted therapies with oral tyrosine kinase inhibitors (TKIs) in 
advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, 
erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more 
favorable outcomes compared with traditional cytotoxic agents. In addition, 
mutations leading to resistance to first-line EGFR and ALK TKIs can now be 
successfully inhibited by soon to be approved third-generation EGFR TKIs 
(osimertinib, rociletinib) and second-generation ALK TKIs (ceritinib, 
alectinib). Notably, increasing feasibility, accessibility, and application of 
molecular profiling technologies has permitted dynamic growth in the 
identification of actionable driver oncogenes. Emerging genomic aberrations for 
which TKIs have shown impressive results in clinical trials and expansion of 
drug labels for approved agents are awaited include ROS1 rearrangements (1-2% of 
tumors, drug: crizotinib) and BRAF-V600E mutations (1-3% of tumors, drugs: 
vemurafenib, dafrafenib + trametinib). Evolving genomic events in which TKI 
responses have been reported in smaller series include MET exon 14 skipping 
mutations (2-4% of tumors, drug: crizotinib); high-level MET amplification (1-2% 
of tumors, drug: crizotinib); RET rearrangements (1% of tumors, drug: 
cabozantinib); and ERBB2 mutations (2-3% of tumors, drug: afatinib), among 
others. Unfortunately, the most common genomic event in NSCLC, KRAS mutations 
(25-30% of tumors), is not targetable with approved or in development small 
molecule inhibitors. Here, we review currently approved, emerging, and evolving 
systemic precision therapies matched with their driver oncogenes for the 
management of advanced NSCLC.