Chronic myeloid leukemia (CML) and its treatment is the prototype of translational research and success of targeted therapy. It was the first disease with a definitive molecular marker where specific targeted small molecular inhibitors, tyrosine kinase inhibitors (TKIs), changed dramatically the course and prognosis from a fatal disease into one with nearly normal survival. TKIs in clinical use are imatinib, nilotinib, dasatinib, bosutinib and ponatinib. Asciminib is a newly developed allosteric BCR-ABL1 inhibitor. Clinicians can personalize treatment based on the toxicity profile of TKIs, taking into account patients’ age, comorbidities and lifestyle. Despite the revolution in the treatment and prognosis of CML in the last 3 decades we are still facing some challenges: Vascular adverse events have emerged as a serious side effect of some TKIs and treatment, especially of elderly patients, and this should be taken into consideration. While treatment of chronic phase CML is considered a great success, coping with accelerated and especially blastic phase CML is still a big challenge. The role of allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI) in 2024 is minor but still relevant for some patients. Future treatments combining TKIs with checkpoint inhibitors as well as interferon or asciminib are under investigation. The issue of deep molecular response (DMR) and its implications for treatment discontinuation and treatment free remission (TFR) – who, when and why, has clinical as well as emotional and financial considerations. Matters of quality of life (QOL) and patient reported outcome measures (PROMs) are now in the forefront once the disease changed its course from a fatal to a chronic and even curable one. And finally, can we look into a crystal ball to predict at the outset who will respond to therapy, who will achieve DMR and who will benefit from prolonged TFR and cure.