We have investigated long-lasting enhancement of signaling effectiveness in the tail sensory neurons of Aplysia using both intracellular and extracellular stimulation. The pairing of high frequency homosynaptic activation with heterosynaptic modulation produced significantly greater enhancement of monosynaptic connections to identified motor neurons than did homosynaptic activity, heterosynaptic modulation, or test stimuli alone. Enhancement of the monosynaptic excitatory postsynaptic potential produced by pairing persisted for at least 4 hr, and the kinetics of decay of this potentiation indicated a time constant of about 5 hr. Although unpaired stimulation produced much weaker enhancement, both homosynaptic activity and heterosynaptic modulation alone produced enhancement lasting more than 90 min. The results are consistent with the possibility that intrinsic electrical activity can amplify the modulatory effects of a paired extrinsic chemical signal to produce long-term changes in synaptic strength. Paired stimulation also produced a relative enhancement of the excitability of the sensory neuron soma as judged by changes in action potential threshold. The lack of generalized changes in the postsynaptic cell and the observation of pairing-induced long-term changes in action potential threshold in the presynaptic cell soma suggest that long-term enhancement produced by pairing has a presynaptic locus in this system. Since pairing-specific enhancement can encode associations between sensory and motivational events in these cells, this form of plasticity may function as a form of associative memory. Similarities between long- term paired enhancement in this system and associative long-term potentiation in other systems suggest that activity-dependent neuromodulation might be involved in cellular memory in other systems as well.