Sympathetic neurons undergoing programmed cell death after nerve growth factor (NGF) deprivation are shown to exhibit a protein synthesis–dependent, BAX-dependent loss of cytochrome c from the mitochondria. However, cytoplasmic microinjection of cytochrome c was insufficient to induce cell death in NGF-maintained sympathetic neurons. In contrast, microinjection of cytochrome c rapidly induced a caspase-dependent death in NGF-deprived, Bax-deficient or NGF-deprived, cycloheximide-treated neurons. Cells needed to be deprived of NGF for 15–20 hr before they acquired competence to die with injection of cytochrome c. These data suggest that NGF deprivation induced the translocation of cytochrome c and another event, which we term as competence-to-die, that was independent of macromolecular synthesis and BAX function. Both these processes were required for neurons to undergo apoptosis.