Estrogen receptor (ER) signaling has been widely studied in a variety of solid tumors, where the differential expression of ERα and ERβ subtypes can impact prognosis. ER signaling has only recently emerged as a target of interest in acute myeloid leukemia (AML), an aggressive hematological malignancy with sub-optimal therapeutic options and poor clinical outcomes. In a variety of tumors, ERα activation has proliferative effects, while ERβ targeting results in cell senescence or death. Aberrant ER expression and hypermethylation have been characterized in AML, making ER targeting in this disease of great interest. This review describes the expression patterns of ERα and ERβ in AML and discusses the differing signaling pathways associated with each of these receptors. Furthermore, we assess how these signaling pathways can be targeted by various selective estrogen receptor modulators to induce AML cell death. We also provide insight into ER targeting in AML and discuss pending questions that require further study.