FMS-Like-Tyrosine kinase-3 (FLT3) mutations are found in about 30% of cases of acute myeloid leukemia and confer an increased relapse rate and reduced overall survival. Targeting this tyrosine kinase by direction inhibition is the focus of both preclinical and clinical research in AML. Several molecules in clinical development inhibit FLT3, but thus far clinical responses have been limited. Correlative studies from monotherapy trials have established that responses require sustained, effective FLT3 inhibition in vivo. Studies combining FLT3 inhibitors with chemotherapy have demonstrated increased remission rates to date but have yet to produce a survival advantage. Currently the only approved FLT3 inhibitor available for off-label use is sorafenib, which clearly has clinical activity but does not commonly lead to a complete response. Several FLT3 inhibitors are currently being tested as single agents and in combination with chemotherapy, and it seems likely that a clinically useful drug will eventually emerge.