Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InsP₃R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP₃R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InsP₃R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP₃R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP₃R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.