Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), significantly improving patient outcomes, particularly in the chronic phase (CML-CP). First-generation TKI imatinib and second-generation TKIs such as dasatinib and nilotinib have proven highly effective, achieving deep molecular responses like major molecular response (MMR). However, resistance or intolerance to TKIs results in treatment failure in 20%–25% of cases, despite an initial good response. Methods: This clinical study involved ten CML patients, aged between 38 and 83 years, including 6 males and 4 females, receiving TKI therapy at our clinic. Patients were treated with imatinib, dasatinib, or nilotinib, depending on insurance approval. BCR-ABL levels were monitored through regular PCR tests, with relapse defined as a 10-log increase from a previous level. Potential causes of relapse, including non-compliance, side effects, and resistance development, were identified through medical records, patient interviews, and consultations. Results: The study analyzed the causes of relapse in ten CML patients treated with TKIs: Patient 1: Noncompliance and developed resistance to dasatinib, so was switched to imatinib, eventually achieving remission. Patient 2: Switched from dasatinib to nilotinib for pleural effusion, achieving undetectable BCR-ABL levels. Patient 3: Stable on imatinib with steady BCR-ABL levels. Patient 4: Switched from dasatinib to nilotinib due to heavy vaginal bleeding. Patient 5: Reached negative BCR-ABL on nilotinib, then switched to dasatinib due to GI side effects. Patient 6: Responded well, BCR-ABL undetectable on Scemblix. Patient 7: Non-compliance due to side effects of vomiting and nausea led to erratic BCR-ABL levels, switched from nilotinib to dasatinib, eventually achieving remission. Patient 8: Non-compliance on imatinib due to insurance problems. Stable after switching from imatinib to nilotinib due to progression. Patient 9: Non-compliant, fluctuating BCR-ABL levels. Patient 10: Positive response to nilotinib, with significant reduction in BCR-ABL levels. Conclusion: CML is a highly treatable hematological cancer with the use of TKIs. We employ highly sensitive PCR tests to detect even the slightest molecular relapse. Our study revealed that 7 out of 10 patients experienced a molecular relapse at some point during their treatment. The primary cause of relapse was non-compliance, followed by side effects, and, although rare, resistance to TKIs. Therefore, patient education and effective communication during consultations are crucial components of treatment.