The medial prefrontal cortex (mPFC) of the rat plays an essential role in behavioral flexibility, as lesions or inactivations of this region impair shifting between strategies or attentional sets using a variety of different behavioral tests. In the present study, we assessed the effects of inactivation of the mPFC on strategy set-shifting and reversal learning, using a novel, automated procedure conducted in an operant chamber. In Experiment 1, inactivation of the mPFC with bupivacaine did not impair the initial learning of a visual-cue (i.e.; always press the lever with a cue light illuminated above it) or a response (i.e.; always press the left lever) discrimination. Control rats required greater number of trials to shift from using a visual-cue to a response strategy than the opposite shift. mPFC inactivation impaired performance of a visual-cue-response set-shift, but not the easier response-visual-cue shift. In Experiment 2, pre-exposure to the visual-cue stimulus lights increased the difficulty of the response-visual-cue shift, reflected by a greater number of trials required by control rats to achieve criterion relative to those in Experiment 1. Under these conditions, inactivation of the mPFC did impair performance of this set-shift. In contrast, mPFC inactivation did not affect reversal learning of a response discrimination. These findings highlight the utility of this automated procedure for assessing set-shifting mediated by the mPFC. Furthermore, they reveal that the relative difficulty of the type of shift rats are required to perform has a direct impact on whether or not the mPFC contributes to this form of behavioral flexibility.