We have examined the effect of cytosolic calcium concentration ([Ca2+]i) on neurite outgrowth in two neuronal cells, cerebellar granule cells and N1E-115 neuroblastoma cells. The set point [Ca2+]i in unstimulated cells bathed in normal extracellular medium was 37 nM and 108 nM, respectively. When we altered extracellular calcium concentration to cause small excursions of [Ca2+]i either above or below the set point, neurite outgrowth from granule cells declined. Thus granule cells show the bell-shaped dependence of neurite outgrowth on [Ca2+]i characteristic of sensory and other neurones [Dev. Brain Res., 70 (1992) 287-290; The Axon, Oxford University Press, New York, 1994]. In contrast, neurite outgrowth from N1E-115 cells increased monotonically as [Ca2+]i was reduced. This result, which is consistent with results obtained by studying individual growth cones [J. Neurosci., 9 (1989) 4007-4020], implies that these transformed cells are aberrant in having no bell-shaped dependence of neurite outgrowth on [Ca2+]i. In both cell types an increase of [Ca2+]i above the set point reduced neurite outgrowth. However, this decline did not persist as [Ca2+]i was set to increasingly high levels by increasing extracellular calcium. Rather, in both cell types, an increase of extracellular calcium above 6.9 mM produced a second, increasing phase of neurite outgrowth.