Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy, driven by the pathognomonic oncogenic fusion protein BCR::ABL1. Tyrosine kinase inhibitors (TKIs) targeting ABL1 have increased the life expectancy of patients with CML to near levels of age-matched healthy individuals. Intriguingly, the response to TKIs varies substantially and is related to observations that CML leukemic stem cells (LSCs) are less sensitive to TKIs. LSC-derived suboptimal response is suggested to explain failing treatment free remission (TFR) in approximately 60% of patients after stopping TKI treatment. Identification of novel and druggable targets on CML LSCs is a possible pathway for increasing TFR. Here we will focus on the role of CML LSCs in initial patient response to TKI therapy, and the possible interactions that LSC may experience in the bone marrow stroma. Adaptation of LSC and stroma is likely to play a central role in the heterogenous responses. Even if overall survival in CML is outstanding, deeper understanding of LSC biology may help more patients to avoid life-long therapy.