Obatoclax, also known as GX15-070, is a novel Bcl-2 homology domain-3 (BH3) mimetic. It occupies a hydrophobic cleft within the BH3 binding groove of Bcl-2, antagonizing Bcl-2 and thus inducing apoptosis. Obatoclax inhibited primary acute myeloid leukemia (AML) progenitor cell proliferation with an average IC50 of 0.18 ± 0.07 µM, and it potently induced apoptosis in primary AML cells with an average IC50 of 3.6 ± 1.2 µM. Obatoclax overcomes Bcl-2-, Bcl-xL-, Bcl-w-, and Mcl-1-mediated resistance to BAX or BAK and to the proteasome inhibitor bortezomib.