Spontaneous and impulse-evoked synaptic currents were observed immediately following nerve-muscle contact in Xenopus cell cultures. The functional significance of this early synaptic activity was examined. Stimulation of pre- and/or post-synaptic cells was found to exert immediate and persistent effects on the efficacy of synaptic transmission. Exogenous application of calcitonin gene-related peptide (CGRP) and neurotrophins, factors that may be coreleased with ACh in activity-dependent manner at the developing neuromuscular junctions, also modulate either the postsynaptic ACh response or presynaptic ACh release. These results underscore the plasticity of developing neuromuscular synapses and suggest a complex interplay between electrical activity and chemical factors during the formation and maturation of neuronal connections.