Genetic approaches in Drosophila have advanced our understanding of the molecular mechanisms of different forms of learning, including habituation, but relevant neural components have not been explored. We show that a well defined neural circuit that underlies an escape response can be habituated, providing for the first time excellent opportunities for studying physiological parameters of learning in a functional circuit in the fly. Compared with other forms of conditioning, relatively little is known of the physiological mechanisms of habituation. The giant fiber pathway mediates a jump-and-flight escape response to visual stimuli. The jump may also be triggered electrically at multiple sites in the tethered fly. This response shows parameters of habituation, including frequency-dependent decline in responsiveness, spontaneous recovery, and dishabituation by a novel stimulus, attributable to plasticity in the brain. Mutations of rutabaga that diminish cAMP synthesis reduced the rate of habituation, whereas dunce mutations that increase cAMP levels led to a detectable but moderate increase in habituation rates. Surprisingly, habituation was extremely rapid in dunce rutabaga double mutants. This corresponds to the extreme defects seen in double mutants in other learning tasks, and demonstrates that defects of the rutabaga and dunce products interact synergistically in ways that could not have been predicted on the basis of simple counterbalancing biochemical effects. Although habituation is localized to afferents to the giant fiber, cAMP mutations also affected performance of thoracic portions of the pathway on a millisecond time scale that did not account for behavioral plasticity. More significantly, spontaneous recovery and dishabituation were not as clearly affected as habituation in mutants, indicating that these processes may not overlap entirely in terms of cAMP-regulating mechanisms. The analysis of habituation of the giant fiber response in available learning and memory mutants could be a crucial step toward realizing the promise of memory mutations to elucidate mechanisms in neural circuits that underlie behavioral plasticity.