In the past few years, our improved understanding of the pathogenesis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has led to remarkable advances in the development of novel therapeutic approaches for these diseases. This chapter summarizes the available clinical data with immune-based therapeutic modalities in AML and MDS, focusing on monoclonal antibodies, T cell engager antibodies, chimeric antigen receptor (CAR)-T cells, and checkpoint blockade via blockade of PD-1/PD-L1 or CTLA4. Numerous clinical trials are currently ongoing in patients with AML and MDS, both in the frontline and relapsed refractory setting. Given the natural diversity of AML blasts, it became apparent that the best responses would be achieved with rationally designed combination strategies of immune therapy, molecular therapy, and chemotherapy. A number of such combinations are enrolling patients with AML in various clinical settings. Biomarkers to select the optimal combination regimen for individual patients are critical.