Regulatory focus theory [Higgins, E. T. Beyond pleasure and pain. American Psychologist, 52 , 1280–1300, 1997] postulates two social-cognitive motivational systems, the promotion and prevention systems, for self-regulation of goal pursuit. However, the neural substrates of promotion and prevention goal activation remain unclear. Drawing on several literatures, we hypothesized that priming promotion versus prevention goals would activate areas in the left versus right prefrontal cortex (PFC), respectively, and that activation in these areas would be correlated with individual differences in chronic regulatory focus. Sixteen participants underwent functional magnetic resonance imaging while engaged in a depth-of-processing task, during which they were exposed incidentally to their own promotion and prevention goals. Task-related cortical activation was consistent with previous studies. At the same time, incidental priming of promotion goals was associated with left orbital PFC activation, and activation in this area was stronger for individuals with a chronic promotion focus. Findings regarding prevention goal priming were not consistent with predictions. The data illustrate the centrality of self-regulation and personal goal pursuit within the multilayered process of social cognition.