Introducing tyrosine kinase inhibitors (TKIs) has had a transformative impact on treating chronic myeloid leukemia (CML), leading to a remarkable survival rate exceeding 80%. The primary focus of CML treatment has centered around enhancing the effectiveness and specificity of TKIs to inhibit the activation of the BCR-ABL1 kinase and addressing resistance arising from mutations in the BCR-ABL1 oncogene. However, despite successful BCR-ABL1 inhibition, a significant number of patients develop resistance to TKIs, necessitating the exploration of novel therapeutic approaches. This review is focused on a detailed examination of the latest reports on both BCR-ABL1-dependent and BCR-ABL1-independent mechanisms of resistance to TKI. The investigation of these crucial pathways could lead to the development of promising therapeutic approaches. By employing such combination treatments, residual leukemic cells can be effectively targeted, leading to an increased response rate among CML patients.