The present experiments determined whether temporary inactivation or blockade of muscarinic cholinergic receptors in the dorsomedial striatum affects acquisition or reversal learning of a response discrimination. Testing occurred in a modified cross-maze across two consecutive sessions. In the acquisition phase, a rat learned to make a turn to the left or to the right for 10 consecutive correct choices. In the reversal learning phase, a rat learned to turn in the opposite direction as required during acquisition for 10 consecutive correct choices. Experiment 1 investigated the effects of the local anesthetic, 2% bupivacaine, infused into the dorsomedial striatum on acquisition and reversal learning. Experiment 2 examined the effects of the muscarinic cholinergic antagonist, scopolamine injected into the dorsomedial striatum on acquisition and reversal learning. Bupivacaine infusions did not impair acquisition, but did impair reversal learning of the response discrimination. Analysis of the errors indicated that the deficit was not due to perseveration of the previously learned strategy, but to an inability to learn the new strategy. Bilateral injections of scopolamine, 1 or 8 microg/side, did not affect acquisition. Infusions of scopolamine at 8 microg, but not 1 microg, produced a reversal learning deficit. The scopolamine-induced deficit resulted from an inability to learn the new strategy. The results suggest that the dorsomedial striatum is important for behavioral flexibility and that activation of muscarinic cholinergic receptors in this region may facilitate the learning of situationally adaptive response patterns.