The present experiments investigated the role of the prelimbic–infralimbic areas in behavioral flexibility using a place–response learning paradigm. All rats received a bilateral cannula implant aimed at the prelimbic–infralimbic areas. To examine the role of the prelimbic–infralimbic areas in shifting strategies, rats were tested on a place and a response discrimination in a cross-maze. Some rats were tested on the place version first followed by the response version. The procedure for the other rats was reversed. Infusions of 2% tetracaine into the prelimbic–infralimbic areas did not impair acquisition of the place or response discriminations. Prelimbic–infralimbic inactivation did impair learning when rats were switched from one discrimination to the other (cross-modal shift). To investigate the role of the prelimbic–infralimbic areas in intramodal shifts (reversal learning), one group of rats was tested on a place reversal and another group tested on a response reversal. Prelimbic–infralimbic inactivation did not impair place or response intramodal shifts. Some rats that completed testing on a particular version in the cross-modal and intramodal experiments were tested on the same version in a new room for 3 d. The transfer tests revealed that rats use a spatial strategy on the place version and an egocentric response strategy on the response version. Overall, these results suggest that the prelimbic–infralimbic areas are important for behavioral flexibility involving cross-modal but not intramodal shifts.