This review article discusses the resistance mechanisms to osimertinib in patients with advanced *EGFR*-mutated non-small cell lung cancer (NSCLC). Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective for *EGFR* activating mutations and the *EGFR* T790M mutation, which is often acquired after treatment with first- or second-generation EGFR-TKIs. Despite the efficacy of osimertinib, patients inevitably develop resistance, with limited therapeutic options available. The review highlights the high degree of tumor heterogeneity and adaptive cellular signaling pathways in NSCLC, leading to a wide range of resistance mechanisms, including EGFR-dependent and EGFR-independent mechanisms. EGFR-dependent mechanisms include the development of *EGFR* tertiary mutations or amplifications, such as the C797S mutation, which impairs the binding of osimertinib to the mutant EGFR. EGFR-independent mechanisms involve the activation of alternative bypass pathways, aberrant downstream signaling, and histologic transformation. The review also discusses the potential of combining osimertinib with other drugs, such as c-Met inhibitors, MEK inhibitors, and BRAF inhibitors, to overcome resistance. Finally, the article emphasizes the need for further research to better understand the molecular mechanisms of resistance and to develop effective strategies to counteract them.This review article discusses the resistance mechanisms to osimertinib in patients with advanced *EGFR*-mutated non-small cell lung cancer (NSCLC). Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective for *EGFR* activating mutations and the *EGFR* T790M mutation, which is often acquired after treatment with first- or second-generation EGFR-TKIs. Despite the efficacy of osimertinib, patients inevitably develop resistance, with limited therapeutic options available. The review highlights the high degree of tumor heterogeneity and adaptive cellular signaling pathways in NSCLC, leading to a wide range of resistance mechanisms, including EGFR-dependent and EGFR-independent mechanisms. EGFR-dependent mechanisms include the development of *EGFR* tertiary mutations or amplifications, such as the C797S mutation, which impairs the binding of osimertinib to the mutant EGFR. EGFR-independent mechanisms involve the activation of alternative bypass pathways, aberrant downstream signaling, and histologic transformation. The review also discusses the potential of combining osimertinib with other drugs, such as c-Met inhibitors, MEK inhibitors, and BRAF inhibitors, to overcome resistance. Finally, the article emphasizes the need for further research to better understand the molecular mechanisms of resistance and to develop effective strategies to counteract them.