Discrete jumps in knowledge, as exemplified by single-trial learning, are critical to survival. Despite its importance, however, one-trial learning remains understudied. We sought to better understand the brain activity adaptations that track punctuated changes in associative knowledge by studying visual-motor associative learning with functional magnetic resonance imaging. Human and primate neurophysiological studies of feedback-based learning indicate that performance feedback elicits high activity at first that diminishes rapidly with repeated success. Based on these findings we hypothesized a network of brain regions would track the importance of feedback, which is large early in learning and diminishes thereafter. Specifically, based on neurophysiological findings, we predicted that frontal and striatal regions would show a large activation to first trial feedback and a subsequent reduction selective to performance feedback but not stimulus cue presentation. We observed that the striatum and frontal cortex as well as several other cortical and subcortical sites exhibited this pattern. These findings match our prediction for activity in frontal and striatal regions. Furthermore, these observations support the more general hypothesis that a large network of regions participates in the associative process once the behavioral goal is definitively identified by first trial performance feedback. Activity in this network declines upon further rehearsal but only for feedback presentation. We suggest that, based on the timing of this process, these regions participate in binding together stimulus cue, motor response, and performance feedback information into an association that is used to accurately perform the task on after the first trial. © 2012 Elsevier B.V. All rights reserved.