The routine use of next-generation sequencing methods has underscored the genetic and clonal heterogeneity of acute myeloid leukemia (AML), subsequently ushering in an era of precision medicine–based targeted therapies exemplified by the small-molecule inhibitors of FLT3, IDH1/IDH2, and BCL2. This advent of targeted drugs in AML has broadened the spectrum of antileukemic therapies, and the approval of venetoclax in combination with a hypomethylating agent has been a welcome addition to our AML patients unable to tolerate intensive chemotherapy. Mounting evidence demonstrates that molecularly targeted agents combined with epigenetic therapies exhibit synergistic augmented leukemic cell kill compared to single-agent therapy. With such great power comes greater responsibility in determining the appropriate frontline AML treatment regimen in a molecularly defined subset and identifying safe and effective combination therapies with different mechanisms of action to outmaneuver primary and secondary resistance mechanisms in AML.

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