5-Hydroxytryptamine (5-HT) transmission has been implicated in memory and in depression. Both 5-HT depletion and specific 5-HT agonists lower memory performance, while depression is also associated with memory deficits. The precise neuropharmacology and neural mechanisms underlying these effects are unknown. We used neural network simulations to elucidate the neuropharmacology and network mechanisms underlying 5-HT effects on memory. The model predicts that these effects are largely dependent on transmission over the 5-HT1A and 5-HT3 receptors, which regulate the selectivity of retrieval. It also predicts differential memory deficit profiles for 5-HT depletion and overactivation. The latter predictions were confirmed in studies with healthy and depressed participants undergoing acute tryptophan depletion or ipsipirone challenge. The results suggest that the memory impairments in depressed subjects may be related to 5-HT undertransmission, and support the notion that 5-HT1A agonists ameliorate memory deficits in depression.