Tyrosin kinase inhibitors (TKI), have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to an impressive increase in overall survival rates and allowing many CML patients to achieve a close-to-normal life expectancy. Unfortunately, there is growing evidence that these drugs are not curative, about 30-35% of the patients who receive imatinib become resistant or discontinue the drug because of side effects; moreover, 15% of all patients become resistant to all TKIs, a condition which represents the biggest challenge in CML treatment. Recent progresses in CML stem cell biology have identified new agents and therapeutic strategies that can be used to target the CML stem cell compartment. These studies have opened new perspectives and have highlighted key strategies for treating, and possibly curing, CML in the upcoming years.