The biochemical basis for most of the morphological changes associated with apoptosis can be traced directly or indirectly to the actions of caspases, a family of intracellular cysteine proteases that function as effectors of programmed cell death (1, 2). Much of the recent progress toward mapping pathways for caspase activation has come from evaluations of normal dividing cells or established tumor lines, where obtaining large numbers of cells for biochemical analysis or transferring genes for functional analysis is readily possible. But, do all types of animal cells contain the same wiring instructions when it comes to connecting steps in cell suicide pathways? Researchers studying cell death in the heart are beginning to probe this question, and they are finding some surprises. Adult cardiac myocytes are terminally differentiated, postreplicative cells whose intimate connections to each other are needed for establishing harmony of electrical conduction and contractile function. The cytosol of these highly specialized cells and their close counterparts within skeletal muscle contains probably the highest density of mitochondria of any tissues, making them unique. Hints that programmed cell death involving muscle cells may occur by routes that differ at least morphologically from other cells have come from studies of intersegmental muscle cell deaths that occur during metamorphosis of the moth, Manduca sexta (3). Moreover, cardiomyocytes do not exhibit the classical nuclear morphology associated with apoptosis in other tissues, even though DNA fragmentation occurs, which often is accepted as a sign of apoptosis (4, 5). It remains unknown whether these differences in morphology reflect fundamentally unique cell suicide programs versus tissue-specific differences in the repertoire of caspases or caspase substrates expressed in muscle cells, such as DFF45 and CIDE family proteins that release associated endonucleases on caspase cleavage (6, 7). One of the events commonly associated with apoptosis involves the participation of mitochondria as caspase activators (8). Mitochondria release cytochrome c (Cyt c) into the cytosol, where it binds to and induces oligomerization of Apaf-1 (9–11), a mammalian homologue of the Caenorhabditis elegans cell death protein CED-4 (12). Once activated by Cyt c, oligomerized Apaf-1 then binds pro-caspase-9, resulting in pro-caspase-9 proteolytic self-processing and activation, followed by caspase-9-mediated cleavage and activation of procaspase-3 (13). Active caspase-3 then both directly participates as a terminal effector of apoptosis by cleaving various substrate proteins and also activates additional pro-caspases. Evidence suggesting a potential difference in the way apoptosis pathways are regulated in adult cardiomyocytes is presented in this issue of the Proceedings by Nurula et al.(14), who studied human heart specimens derived from patients undergoing heart transplantation for ischemic or idiopathicdilated cardiomyopathy. Similar to previous studies (15, 16), these investigators observed occasional cardiomyocytes within diseased hearts that displayed evidence of DNA fragmentation by in situ end-labeling (ie, terminal deoxynucleotidyltransferase-mediated UTP nick end labeling) and gross nuclear morphological changes consistent with an apoptosis-like process. However, although only occasional cells exhibited obvious signs of deterioration, Cyt c release from mitochondria and proteolytic processing of pro-caspase-3 were readily detectable by immunoblot analysis of tissue extracts, implying that mitochondrial permeability barrier function and caspase activation had occurred in a substantial proportion …