The inhibitor of caspase-3– activated DNase (ICAD) is a caspase-3 substrate that controls nuclear apoptosis. ICAD has two isoforms: a functional isoform of M.W. 45kDa, ICAD-L/DNA fragmentation factor (DFF) 45; and a M.W.35kDa isoform, ICAD-S/DFF35. Although both ICAD-L and ICAD-S can bind and inhibit CAD, only ICAD-L was reported to be functional. ICAD is cleaved to be inactivated and allow caspase-activated DNase (CAD) to execute nuclear internucleosomal apoptotic DNA fragmentation. In non-apoptotic cells, CAD is complexed with its inhibitor, ICAD. The activation of the CAD/ICAD complex occurs through the caspase 3-mediated cleavage of ICAD at residues 117 and 224, which results in three ICAD fragments that are then released from CAD. In addition to its DNase inhibitory activity, ICAD acts as a CADspecific folding chaperone. There are recent reports that ICAD is a potential target for restoring a normal apoptotic signal transduction pathway in colon and brain cancer cells.