Cognitive flexibility is a crucial human ability allowing efficient adaptation to changing task challenges. Although a person's degree of flexibility can vary from moment to moment, the conditions regulating such fluctuations are not well understood. Using a task-switching procedure with fMRI, we found several brain regions in which neural activity preceding each trial predicted subsequent cognitive flexibility. Specifically, as pretrial activity increased, performance improved on trials when the task switched but did not improve when the task repeated. Regions from which flexibility could be predicted reliably included the basal ganglia, anterior cingulate cortex, prefrontal cortex, and posterior parietal cortex. Although further analysis revealed similarities across the regions in how flexibility was predicted, results supported the existence of multiple independent sources of prediction. These results reveal distinct neural mechanisms underlying fluctuations in cognitive flexibility.