The treatment landscape for acute myeloid leukemia (AML) has changed substantially since 2017. A host of new targeted drugs have emerged onto the scene, including venetoclax to target BCL-2, midostaurin and gilteritinib to target FLT3 and ivosidenib and enasidenib to target mutant IDH1 and IDH2, respectively. Other additions include re-approval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway and a liposomal formulation of daunorubicin and cytarabine (CPX-351). AML is genomically heterogeneous and has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centred around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by haematologists in this era of new drugs include 1) the timely identification of actionable mutations, not just at diagnosis but also at relapse, 2) deciding which drug to use when several therapeutic options are available and 3) the need for increased awareness of how to anticipate, mitigate and manage common complications associated with these new agents. This new addition to the How I Treat series will utilize three case presentations to discuss some of the new treatment challenges encountered in the management of AML, with the goal of providing practical guidance to aid the practising physician.