FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in AML. Thirty percent of patients with acute myeloid leukemia (AML) harbor activating mutations in FLT3, either internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3 TKD). Small molecule FLT3 inhibitors have emerged as an attractive therapeutic option in patients with FLT3 mutations; however, the clinical activity of early inhibitors was limited by a lack of selectivity, potency and unfavorable pharmacokinetic properties. Newer agents such as quizartinib have improved potency and selectivity associated with much higher bone marrow response rates; however, response duration is limited by the development of secondary resistance. We will review here a number of FLT3 inhibitors that have been evaluated in clinical trials and discuss challenges facing the use of these agents in AML.