Small molecule inhibitors targeting mutant FLT3, IDH1, and IDH2 as well as venetoclax-based combination therapies have expanded treatment options for patients with acute myeloid leukemia (AML). As the landmark trials leading to the approval of FLT3, IDH1, and IDH2 inhibitors in R/R-AML were conducted prior to the widespread use of venetoclax, it is unclear how these results apply in the current era of venetoclax based therapy frequently being used in the frontline treatment of AML. In this multicenter, retrospective cohort study, we included 53 patients who received FLT3, IDH1 or IDH2 inhibitors after disease progression on venetoclax-based therapy. Among patients treated with targeted agents after venetoclax, the overall response rate (ORR; composite of complete remission CR/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 17.7 % (n = 9 patients) and median OS of 4.2 months. Eight of 9 patients responding to targeted agents after venetoclax received gilteritinib. None of the patients with RAS pathway mutations responded to targeted agents after venetoclax. Additionally, mutations in TP53 and KRAS were associated with shorter OS among patients treated targeted agents. Our data suggest that response rates to targeted therapies after venetoclax are low and novel therapeutic strategies are warranted. •FLT3, IDH1, and IDH2 inhibitors after venetoclax have modest activity (ORR: 17 %).•Gilteritinib retained efficacy with ORR of 30 %.•No patient with RAS pathway mutations responded to targeted agents after venetoclax.•Median OS from the time of initiation of FLT3 or IDH1/2 inhibitors was 4.2 months.•Mutations in TP53 and KRAS were associated with shorter OS.