A better understanding of critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non-small-cell lung cancer (NSCLC) has led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Since the introduction of tyrosine kinase inhibitors (TKIs) targeting mutant EGFR, we have witnessed a continued shift towards a biomarker-driven treatment algorithm for patients with advanced-stage NSCLC. The identification of less common oncogene drivers led to a marked reshaping of the diagnostic and therapeutic approach towards NSCLC. The introduction of novel highly selective inhibitors is expanding the use of targeted therapies to rare and ultra-rare subsets of patients, further increasing the therapeutic armamentarium of advanced NSCLC. In this article we will briefly discuss the recent advances for the targeted treatment of advanced NSCLC patients with RET fusions, MET exon14 skipping, HER2 overexpression and KRAS mutations.