These observations have represented the basis for the development of a large number of Tyrosine Kinase Inhibitors (TKIs) with activity against KIT and FLT3. Some of these inhibitors are still in the preclinical phase, but many have been tested in phase I/II/III clinical studies. Although these inhibitors when used as single agents have lead to a significant reduction of the number of leukemic blasts, they have produced only transient and limited clinical responses. This efficacy may be related to the limited inhibitory caefficacy of these inhibitors, occurrence of resistance and to the complexity of the genetic abnormalities occurring in AMLs. However, recently Quizartinib, a potent FLT3 inhibitor, showed an impressive rate of remission induction in patients with chemotherapy-refractory FLT3-ITD-positive AMLs, but most remissions do not meet classical criteria of complete remissions and instead represent clearance of bone marrow blasts with incomplete recovery of blood cell counts. However, the majority of these patients after an initial sustained response exhibit a leukemic relapse due to the rare pre-exisisting or new FLT3-ITD-TKD mutants surviving to the treatment with this drug and becaming driver leukemic clones. The combination of various types of FLT3 TKIs, including a type II TKI like Quizartinib with a type I FLT3 inhibitor efficiently targeting TKD mutants, such as Crenolanib, or the combination of FLT3 inhibitors with other molecularly targeted agents inhibiting other pathways activated in leukemic cells would determine a major progress in leukemia therapy. The efficacy of FLT3 TKIs in combination with standard anti-leukemic chemotherapeutics is also under evaluation in several combination clinical trials. It is expected that these trials could determine an improvement in the negative prognosis of AML patients with FLT3/ITD mutations.