Objectives: Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) represents a high-risk and somewhat diverse subtype of AML, and substantial confusion exists about the pathologic evaluation needed for diagnosis, which can include the patient’s clinical history, cytogenetic analysis, mutational analysis, and/or morphologic evaluation. Treatment decisions based on incomplete or untimely pathology reports may result in the suboptimal treatment of patients with AML-MRC. Methods: Using a PubMed search, diagnosis of and treatment options for AML-MRC were investigated. Results: This article reviews the current diagnostic criteria for AML-MRC, provides guidance on assessments necessary for an AML-MRC diagnosis, summarizes clinical and prognostic features of AML-MRC, and discusses potential therapies for patients with AML-MRC. In addition to conventional chemotherapy, treatment options include CPX-351, a liposomal encapsulation of daunorubicin/cytarabine approved for treatment of adults with AML-MRC; targeted agents for patients with certain mutations/disease characteristics; and lower-intensity therapies for less fit patients. Conclusions: Given the evolving and complex treatment landscape and the high-risk nature of the AML-MRC population, a clear understanding of the pathology information necessary for AML-MRC diagnosis has become increasingly important to help guide treatment decisions and thereby improve patient outcomes.