Long-term potentiation (LTP) refers to a persisting enhancement of neurotransmission that follows high-frequency activation of certain synapses. Although both pre- and postsynaptic mechanisms contribute to LTP, it is believed that the enhanced release of neurotransmitter that accompanies this process results from the production of a diffusible messenger in postsynaptic neurons which traverses the synaptic cleft and alters the function of presynaptic terminals. One candidate for such a messenger is arachidonic acid, a metabolite produced by phospholipase A2 which augments synaptic transmission when coupled with presynaptic stimulation. However, the effects of arachidonic acid require activation of the postsynaptic receptor for N-methyl-D-aspartate. Previously we found that platelet-activating factor (1 O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), another phospholipase A2-derived messenger, selectively enhances excitatory postsynaptic currents in hippocampal neurons by a presynaptic mechanism. We now present evidence that platelet-activating factor, acting at a receptor localized to synaptic regions, participates in LTP in the CA1 region of rat hippocampal slices and may serve as part of a retrograde signalling cascade.