There is accumulating evidence that caspase-independent programs play a significant role in delayed neuronal death following ischemic stroke. Previous research has implicated mitochondrial proteins, such as apoptosis-inducing factor (AIF) and Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP3), as players involved in this pathway. More recent work has begun to hone in on the specific interactions between these molecules and the mediators that might function upstream [e.g., poly(ADP-ribose) polymerase-1 (PARP-1)] and downstream [e.g., endonuclease G (EndoG)] of them. As the study of caspase-independent programs has expanded, it has become increasingly apparent that this pathway is not simply an alternative to apoptosis when caspases are unavailable, but a unique process, distinct from both apoptosis and necrosis. Similar caspase-independent pathways as the ones mentioned apply to organ systems outside of the central nervous system. Put together, the data suggest that caspase-independent programmed cell death is a complex and resilient death program that will likely need to be considered and countered in devising an effective drug therapy for the treatment of ischemic stroke.