In the past decade, antibody-based therapeutics have started to make good on their promise with potent clinical activity in several human malignancies, including acute myeloid leukemia (AML). In this chapter, various classes of antibody- based agents designed to selectively induce apoptotic cell death in AML will be discussed, including naked antibodies, antibody–drug conjugates, and immunotoxins. Moreover, the rationale for exploiting several of the body’s own immune effector molecules for the targeted elimination of AML cells is highlighted. In particular, this involves the use of the death ligand TNF-related apoptosis-inducing ligand (TRAIL). Recombinant fusion proteins in which an antitumor antibody fragment (scFv) is fused to soluble TRAIL proved to be essentially inactive while en route, but gain potent pro-apoptotic antitumor activity after selective binding to a predefined tumor-associated cell surface antigen. The use of death ligand fusion proteins may be of clinical significance in targeted approaches in AML.