Highlights Lung cancer is responsible for around 1.8 million deaths per year worldwide and is widely the leading cause of cancer-related mortality. The development of specific inhibitors is currently extending to less common oncogenic drivers (i.e., ROS1, MET, RET, NTRK, HER2, and BRAF) with an exponential growth of dedicated clinical trials. While, individually, each of these drivers appears with low prevalence, altogether, they account for 15% of all lung cancer cases, thereby affecting a large population of patients worldwide. Similar to what is observed with most targeted therapies directed against an oncogenic driver, the initial clinical response to targeted kinase inhibitors is almost always temporary and acquired resistance to these drugs invariably emerges, restricting their clinical utility. The characterization of intrinsic and acquired resistance relies on tissue or liquid biopsy upon disease progression. However genomic testing does not always capture the underlying mechanism of resistance. Both on-target and off-target resistance mechanisms to targeted therapies could be tackled in the clinic but the design of the most effective treatment still requires further evaluation. The discovery of oncogenic driver mutations led to the development of targeted therapies with non-small cell lung cancer (NSCLC) being a paradigm for precision medicine in this setting. Nowadays, the number of clinical trials focusing on targeted therapies for uncommon drivers is growing exponentially, emphasizing the medical need for these patients. Unfortunately, similar to what is observed with most targeted therapies directed against a driver oncogene, the clinical response is almost always temporary and acquired resistance to these drugs invariably emerges. Here, we review the biology of infrequent genomic actionable alterations in NSCLC as well as the current and emerging therapeutic options for these patients. Mechanisms leading to acquired drug resistance and future challenges in the field are also discussed.