Sympathetic neuronal apoptosis after nerve growth factor (NGF) deprivation requires the activation of two events: a protein synthesis-dependent, Bax-dependent release of mitochondrial cytochrome c and a protein synthesis-independent, Bax-independent development of competence. Unlike in most cells, cytosolic cytochrome c is not sufficient to induce cell death in NGF-maintained sympathetic neurons but can do so in neurons that have developed competence. We report that cytosolic cytochrome c-induced apoptosis in competent sympathetic neurons is completely dependent on caspase-9. In addition, the neuroprotective agents KCl and chlorophenylthio-cAMP are potent inhibitors of the development-of-competence pathway in NGF-deprived sympathetic neurons. We also find that the development of competence is reversible. Readdition of NGF reverses competence, and neurons can regain their resistance to cytosolic cytochrome c. Importantly, we examined the mechanism of development of competence and report that the inability of cytochrome c to activate caspases in NGF-maintained sympathetic neurons can be overcome with exogenous Smac that inhibits the inhibitor of apoptosis (IAP) family of proteins. Microinjection of cytochrome c and Smac, but neither alone, induces rapid cell death in NGF-maintained neurons. These data suggest that development of competence may be the result of the loss of the function of one or more members of the IAP family of caspase inhibitors that is needed before cytochrome c can activate caspases and induce cell death in neurons.