About half the neurons in the brain die at the time when their connections are being formed. This neuronal death is regulated by anterograde and retrograde signals that reflect both electrical activity and the uptake of trophic factors. Our recent data on the isthmo-optic projection indicate that there are in fact two different retrograde signals: a slow-acting survival signal mediated by a neurotrophin, and a fast-acting death signal mediated by calcium entry due to electrical activity in the presynaptic terminals. The developmental roles of the cell death are not well understood, but they appear to include the elimination of aberrant connections. The intracellular mechanisms of the cell death may not always correspond to the apoptotic ones so thoroughly investigated in vitro, because only one of the three morphological types occurring regularly in vivo resembles apoptosis. However, our experiments on retinal ganglion cells indicate that several apoptotic mechanisms apply in this particular in vivo situation: these include an involvement of oxygenated free radicals and glutathione, cell cycle-related events, and probably the synthesis of proteins promoting neuroprotection or cell death.