Acute myeloid leukemia (AML) is an aggressive disease of clonal hematopoiesis with a high rate of relapse and refractory disease despite intensive therapy. Traditionally, relapsed or refractory AML has increased therapeutic resistance and poor long-term survival. In recent years, advancements in the mechanistic understanding of leukemogenesis have allowed for the development of targeted therapies. These therapies offer novel alternatives to intensive chemotherapy and have prolonged survival in relapsed or refractory AML. Unfortunately, a significant portion of patients do not respond to these therapies and relapse occurs in most patients who initially responded. This review focuses on the mechanisms of resistance to targeted therapies in relapsed or refractory AML.