Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) bring significant benefits to non-small cell lung cancer patients with EGFR mutations, which represent a breakthrough in lung cancer therapy. However, patients will ultimately develop the acquired resistance to the first- or second-generation EGFR-TKIs after a period of treatment, and EGFR T790M mutation is the most common resistant mechanism. The third-generation EGFR-TKIs target T790M mutation and show potent anti-tumor efficacy, especially in central neural system response. Unfortunately, patients inevitably get resistant to the third-generation EGFR-TKIs due to various mechanisms, which can be mainly divided into EGFR-dependent and -independent ones. EGFR-dependent mechanism refers to manifold EGFR mutations while EGFR-independent mechanisms include bypass signal activation, histologic transformation and so on. To precisely address this issue and improve clinical outcomes, various other therapies (e.g. chemotherapy, radiotherapy, etc.) in combination with the third-generation EGFR-TKIs are designed. However, the current results of combination therapies are insufficient and ambiguous, which remain further exploration. Herein, we provide an updated landscape of the third-generation EGFR-TKIs and elaborate on the complex resistant mechanisms. Notably, we summarize the combination therapies with third-generation EGFR-TKIs and discuss their limitations and future perspective, aiming at providing insights to clinicians from bench to bedside.