Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) that is highly selective for EGFR mutations, including the T790M resistance mutation, in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite its efficacy in first- and second-line settings, resistance develops in most patients, with limited therapeutic options beyond chemotherapy and local ablative therapy. Resistance mechanisms are heterogeneous, encompassing both EGFR-dependent and independent pathways. Resistance mechanisms vary depending on whether osimertinib is used as first-line or second-line therapy, reflecting differences in selection pressure and clonal evolution. This review summarizes the molecular mechanisms of resistance to osimertinib in patients with advanced EGFR-mutated NSCLC, including MET/HER2 amplification, activation of the RAS-MAPK or RAS-PI3K pathways, novel fusion events, and histological/phenotypic transformation. It also discusses current evidence regarding potential new approaches to counteract osimertinib resistance. Osimertinib has shown significant efficacy in both first-line and second-line settings, with the AURA trial demonstrating an ORR of 61% and median PFS of 9.6 months in patients with T790M mutations. The AURA3 trial confirmed its superiority over platinum-based chemotherapy, with a median PFS of 10.1 months and ORR of 71%. Osimertinib is also effective in central nervous system (CNS) metastases, with a median CNS PFS of 11.7 months compared to 5.6 months with chemotherapy. The FLAURA trial demonstrated its efficacy in first-line treatment, with a median PFS of 18.9 months compared to 10.2 months with first-generation TKIs. Resistance to osimertinib can occur through various mechanisms, including EGFR-dependent mutations such as C797S, G796R, L792H, L718Q, and G724S, as well as EGFR-independent mechanisms such as MET amplification, HER2 amplification, RAS-MAPK pathway activation, PI3K pathway activation, and oncogenic fusions. Resistance mechanisms can also involve histologic transformation to small-cell lung cancer (SCLC) or epithelial-to-mesenchymal transition (EMT). These mechanisms are often complex and heterogeneous, contributing to the challenge of overcoming resistance. Therapeutic strategies to overcome osimertinib resistance include the use of fourth-generation EGFR-TKIs, combination therapies with other TKIs or targeted agents, and the use of MEK inhibitors or AXL inhibitors. Clinical trials are ongoing to evaluate the effectiveness of these approaches. Additionally, the use of liquid biopsy and next-generation sequencing is being exploredOsimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) that is highly selective for EGFR mutations, including the T790M resistance mutation, in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite its efficacy in first- and second-line settings, resistance develops in most patients, with limited therapeutic options beyond chemotherapy and local ablative therapy. Resistance mechanisms are heterogeneous, encompassing both EGFR-dependent and independent pathways. Resistance mechanisms vary depending on whether osimertinib is used as first-line or second-line therapy, reflecting differences in selection pressure and clonal evolution. This review summarizes the molecular mechanisms of resistance to osimertinib in patients with advanced EGFR-mutated NSCLC, including MET/HER2 amplification, activation of the RAS-MAPK or RAS-PI3K pathways, novel fusion events, and histological/phenotypic transformation. It also discusses current evidence regarding potential new approaches to counteract osimertinib resistance. Osimertinib has shown significant efficacy in both first-line and second-line settings, with the AURA trial demonstrating an ORR of 61% and median PFS of 9.6 months in patients with T790M mutations. The AURA3 trial confirmed its superiority over platinum-based chemotherapy, with a median PFS of 10.1 months and ORR of 71%. Osimertinib is also effective in central nervous system (CNS) metastases, with a median CNS PFS of 11.7 months compared to 5.6 months with chemotherapy. The FLAURA trial demonstrated its efficacy in first-line treatment, with a median PFS of 18.9 months compared to 10.2 months with first-generation TKIs. Resistance to osimertinib can occur through various mechanisms, including EGFR-dependent mutations such as C797S, G796R, L792H, L718Q, and G724S, as well as EGFR-independent mechanisms such as MET amplification, HER2 amplification, RAS-MAPK pathway activation, PI3K pathway activation, and oncogenic fusions. Resistance mechanisms can also involve histologic transformation to small-cell lung cancer (SCLC) or epithelial-to-mesenchymal transition (EMT). These mechanisms are often complex and heterogeneous, contributing to the challenge of overcoming resistance. Therapeutic strategies to overcome osimertinib resistance include the use of fourth-generation EGFR-TKIs, combination therapies with other TKIs or targeted agents, and the use of MEK inhibitors or AXL inhibitors. Clinical trials are ongoing to evaluate the effectiveness of these approaches. Additionally, the use of liquid biopsy and next-generation sequencing is being explored