Non-small cell lung cancer (NSCLC), since the recognition of epidermal growth factor receptor (EGFR) mutations that sensitized tumors to EGFR tyrosine kinase inhibitors, has been a poster child for precision oncology in solid tumors. The emergence of resistance to the EGFR tyrosine kinase inhibitors led to the unveiling of multiple resistance mechanisms that are now recognized to be frequent mechanisms across multiple tumor types. Coevolution of technological advancements in testing methods available to clinical laboratories now has identified a growing number of molecularly defined subsets of NSCLC that have new therapeutic implications. In addition, identifying patients eligible for immunotherapy is another goal for precision oncology. Recently, studies suggest that TMB may be a promising biomarker for selecting patients with NSCLC for immunotherapy. This review focuses on emerging potentially targetable alterations specifically in RET, ERBB2 (HER2), MET, and KRAS and current evidence and controversies surrounding TMB testing.