Acute myeloid leukemia (AML) is an uncontrolled clonal proliferation of undifferentiated myeloid stem cells leading to an accumulation of immature myeloblasts. For over the past three decades, the gold standard induction therapy in AML consisted of a cytarabine and anthracycline-based chemotherapy regimen (e.g., “7+3”). However, relapse and refractory (R/R) disease remains an issue despite this long-standing therapy, with a median overall survival of less than 6 months. Various factors have been associated with worsening outcomes including age greater than 65 years, unfavorable cytogenetics, and a first complete remission duration of less than 12 months. Treatment of R/R AML is associated with low remission rates after first salvage therapy, further declining with subsequent lines of therapy. The only curative salvage option for R/R patients is hematopoietic stem cell transplant, but due to high risk of mortality, many patients are not eligible for this approach. With scientific advancements seen in recent years, new treatment modalities have been developed. In this chapter, we will review the novel treatment options that have demonstrated promising results, including targeted therapies (e.g., Fms-like tyrosine kinase 3, isocitrate dehydrogenase 1 and 2, BCL2 inhibitors), monoclonal antibodies (e.g., anti-CD33, anti-CD47, anti-CD123), and immunotherapies (e.g., PD-1, CTLA4).