The appearance of 5-hydroxytryptamine (serotonin; 5-HT) in the cerebral cortex coincides with developmental events such as cell proliferation, survival, and differentiation. We tested the hypothesis that 5-HT plays a role in these events by examining rat cortical progenitor cells in vitro. Using bromodeoxyuridine incorporation we found that 5-HT did not affect the proliferation of these cells, but a cell survival assay indicated that it promoted their survival. The observed survival effect was mimicked by the 5-HT2a/2c receptor agonist alpha-methyl-5-HT and blocked by the 5-HT2a receptor antagonist cinanserin. Consistent with increased survival was the finding, using the terminal transferase nick end labeling method, of reduced cell death in cultures exposed to 5-HT. Immunohistochemical analysis with cell-specific markers revealed that the effect of 5-HT was directed specifically to the glutamate-containing neuronal population and not to any other cortical cell types. These results indicate that 5-HT does not exert its effects on dividing neuroepithelial cells in the developing cortex, but rather on postmitotic neurons.