Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of an oncogenic fusion gene, BCR–ABL1. This fusion gene produces a cytoplasmic protein with tyrosine kinase activity that acts as a main driver of oncogenesis and abnormal proliferation of myeloid cells in CML. Targeted therapy with BCR–ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib is followed by long-term responses in most patients. However, despite continuous treatment, relapses occur, suggesting the presence of TKI-resistant neoplastic stem cells in these patients. Here, we discuss potential mechanisms and signaling molecules involved in the prosurvival and self-renewal capacity of CML neoplastic stem cells as well as antigens expressed by these cells. Several of these signaling molecules and cell surface antigens may serve as potential targets of therapy and their use may overcome TKI resistance in CML in the future.