<b><i>Background:</i></b> Acute myeloid leukemia (AML) is a biologically heterogenous disease arising in clonally proliferating hematopoietic stem cells. Sequential acquisition of mutations leads to expanded proliferation of clonal myeloid progenitors and failure of differentiation, leading to fulminant AML. <b><i>Summary:</i></b> Here, we review the pathophysiology of AML with a focus on factors predisposing to AML development, including prior chemo- and radiation therapy, environmental factors, and germline predisposition. <b><i>Key Message:</i></b> Increasing genomic characterization of AML and insight into mechanisms of its development will be critical to improvement in AML prognostication and therapy.