Our laboratory has been actively engaged in investigating mechanisms of activation of initiator caspase-9 during hypoxia in the developing newborn and fetal brains. The present review has been organized as follows: (a) the effect of hypoxia on the expression and activation of caspase-3, -8, and -9 in the newborn brain; (b) the role of nitric oxide in caspase-9, and caspase-3 activation during hypoxia in the newborn brain; (c) the role of nuclear Ca(2+)-influx in caspase-9 and caspase-3 activation during hypoxia in the newborn brain; (d) the effect of caspase-9 inhibition during hypoxia on preventing downstream events including caspase-3 activation. The results of our research investigations presented in (b), (c), and (d) elucidate mechanisms of caspase activation during hypoxia in the newborn brain. These studies provide the fundamental framework for developing neuroprotective strategies in the hypoxic newborn.