Indirubins are kinase inhibitory bis-indoles that can be generated from various plant, mollusk, mammalian, and bacterial sources or chemically synthesized. We here report on the synthesis and biological evaluation of 3'-substituted 7-halogenoindirubins. Molecular modeling and kinase assays suggest that steric hindrance prevents 3'-substituted 7-halogenoindirubins from interacting with classical kinase targets of other indirubins such as cyclin-dependent kinases and glycogen synthase kinase-3. Surprisingly 3'-substituted 7-halogenoindirubins induce cell death in a diversity of human tumor cell lines. Although some 3'-substituted 7-halogenoindirubins appear to induce effector caspase-independent, nonapoptotic cell death, others trigger the landmarks of classical apoptosis. A structure-activity relationship study was performed to optimize 3'-substituted 7-halogenoindirubins with respect to solubility and cell death induction. Despite their unidentified targets, 3'-substituted 7-halogenoindirubins constitute a new promising family of antitumor agents.