Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, and it tends to have a poor prognosis. For NSCLC with EGFR gene mutation, the tyrosine kinase inhibitor osimertinib can be an effective targeted therapy. However, patients usually develop resistance to osimertinib over time, often due to additional changes in the EGFR gene. For example, tumors can develop mutations in exons 18 and 20 of EGFR that reduce osimertinib's ability to bind to its target. In addition, the EGFR gene can become amplified, leading to extra copies in the genome. This leads to abnormally high amounts of the EGFR protein, overwhelming osimertinib and triggering signaling pathways that promote cancer progression. Over time, tumor cells with resistance-promoting mutations can replace the original drug-sensitive cells that are killed off by osimertinib. Combination therapies or next-generation tyrosine kinase inhibitors might help address these limitations of osimertinib. Indeed, the next-generation drugs developed so far have been promising in patients with the most common resistance-promoting mutation, C797S. Nevertheless, standardized solutions to the different types of osimertinib resistance have not yet been determined, emphasizing the urgent need for more research to improve NSCLC outcomes.