In the attempt to evaluate the potential use of the mouse as a model of human cognitive functions and their pathologies, we investigated the contribution of the mouse prefrontal cortex and, more specifically, the prelimbic area, in a serie of behavioral paradigms of increasing difficulty up to the ability to show flexible oriented behaviors, a highly adaptative function exhibited by mamals when confronted to changing environments. Using behavioral tasks that emphazied different aspects of conflict management and flexible decision making, we show that mice with prelimbic lesions exhibit sustained difficulties in adapting their behavior when the rule is changing repeatidly or when a highly motivated reinforcement –social interaction after social deprivation- is confronted with exploratory activity. Prelimbic lesion, however, did not prevent a normal exploratory behavior towards novelty per se. Thus, we show that in mice, as in other mamals, the prelimbic cortex controls the flexible behavioral switch between routine actions and novel actions. These results open the way to the study of genetic aspects of such high cognitive control, known to be seriously compromised in numerous psychiatric conditions.