Our behavior is frequently guided by rules, or prescribed guides for action. The prefrontal cortex (PFC) has been implicated in the ability to retrieve and use rules in a conscious, effortful manner. Several functional magnetic resonance imaging (fMRI) studies have examined the role of the PFC in rule representation; however, the precise PFC subregions implicated in this function vary from study to study. This observation raises the question of whether there are distinct classes of rules that are represented differentially in the brain. To address this question, an fMRI study was conducted in which participants performed two tasks, each at two levels of difficulty, during acquisition of event-related fMRI data. The response competition task was based on the Stroop paradigm: Participants were cued to determine either the ink color or color name associated with a word stimulus. In contrast, the paired associates task evaluated participants' memory for either one or four previously memorized pairs of words. On each trial, an instructional cue appeared briefly on the screen, followed by an 8-sec delay and a probe period. The left ventrolateral PFC (VLPFC) and the left supplementary motor area (SMA)/pre-SMA were engaged during the delay period for all conditions, consistent with a general role in rule representation. In contrast, different parts of the dorsolateral PFC, the anterior PFC, and the right VLPFC were preferentially engaged by one or both of the more challenging rules, consistent with the idea that rules are represented by partially distinct brain structures according to their content.