Secondary acute myeloid leukemia (s-AML) is recognized as AML arising from prior hematological disease, usually myelodysplastic syndrome, myeloproliferative neoplasm, or aplastic anemia or has myelodysplasia related changes or develops in context of prior cytotoxic or radiation therapy. Understanding the biology of s-AML is of utmost importance as this portends a high-risk disease including a potential for lower responses to chemotherapy. Some therapeutic developments in recent times have been CPX-351 as well as venetoclax-containing combinations. Of particular ongoing and forthcoming interest is the role of targeted therapy itself or in combination with other agents. Lastly, the role of allogeneic stem cell transplantation remains crucial although debated, and with improvement in treatment strategies provides opportunities to use the two in combination for best results.