Complex problem-solving and planning involve the most anterior part of the frontal lobes including the fronto-polar prefrontal cortex (FPPC), which is especially well developed in humans compared with other primates. The specific role of this region in human cognition, however, is poorly understood. Here we show, using functional magnetic resonance imaging, that bilateral regions in the FPPC alone are selectively activated when subjects have to keep in mind a main goal while performing concurrent (sub)goals. Neither keeping in mind a goal over time (working memory) nor successively allocating attentional resources between alternative goals (dual-task performance) could by themselves activate these regions. Our results indicate that the FPPC selectively mediates the human ability to hold in mind goals while exploring and processing secondary goals, a process generally required in planning and reasoning.