In this review we present recent evidence implicating second-messenger systems in two forms of long-lasting synaptic change seen at crustacean neuromuscular junctions. Crustacean motor axons are endowed with numerous terminals, each possessing many individual synapses. Some synapses appear to be quiescent or impotent, but can be recruited in response to imposed functional demands. Supernormal impulse activity leads to long-term facilitation (LTF) which persists for many hours. During the persistent phase, additional synapses are physiologically effective, and morphological changes in synapses are seen at the ultrastructural level. Pulsatile application of serotonin, a neuromodulator, also enhances synaptic transmission, but this enhancement declines more rapidly than LTF. Elevation of intraterminal Ca2+ is neither necessary nor sufficient for long-lasting enhancement of transmission, but activation of A-kinase is necessary. LTF is set in motion by an unknown depolarization-dependent mechanism leading to A-kinase activation, whereas serotonin facilitation depends for its initiation on the phosphatidylinositol system. The initial phase of serotonin facilitation may be accounted for by production of inositol triphosphate, whereas the secondary long-lasting phase appears to require participation of both C kinase and A kinase. Neither LTF nor serotonin facilitation requires an intact neuron; both are presynaptic phenomena expressed by the nerve terminals. Brief comparison is made with long-lasting synaptic changes in other systems.