Resistance to tyrosine kinase inhibitors (TKIs) has many facets. The causes of resistance include low patient compliance, low plasma or intracellular drug concentration, BCR-ABL1 mutations, and clonal chromosome abnormalities in Ph+ cells, but in at least 50% of patients the causes are currently unknown. Primary resistance occurs when a predefined response level is not achieved within a prespecified period of time. Not achieving a complete hematologic response (CHR) within 3 months, not achieving a partial cytogenetic response and/or a BCR-ABL1 transcripts level ≤10% (international standard) within 6 months, and not achieving a complete cytogenetic response (CCyR) and/or a BCR-ABL1 transcripts level <1% within 12 months, define primary resistance. Secondary resistance is defined by a loss of CHR, or CCyR, or major molecular response. Resistance to imatinib calls without exceptions for a second-generation TKI. In case of resistance to two TKIs, an allogeneic stem cell transplantation should be considered.