Mechanisms of drug resistance in hematologic malignancies can include selection of resistant clones present at very low levels at the time of diagnosis. For instance, in chronic myeloid leukemia (CML), treatment with a tyrosine kinase inhibitor (TKI) such as imatinib can reduce the dominant neoplastic clone (green circles) and permit recovery of normal hematopoiesis (blue circles), but in some cases TKIs also apply selective pressure allowing outgrowth of preexisting neoplastic subclones harboring ABL kinase mutations such as T315I (red circles), which eventually leads to resistance and treatment failure. Targeting of the resistance clone with a third-generation TKI such as ponatinib can lead to long-term remission; it remains to be seen whether earlier treatment with ponatinib will prevent emergence of resistant clones. Similarly, in ALL, the presence of an activating NT5C2 mutation can lead to relapse during 6-MP maintenance therapy and will require use of adjuvant or non-cross-resistant therapies to overcome.