Serotonin-6 (5-HT6) receptors are densely expressed in the dorsolateral striatum (DLS), a brain region linked to habits. Medications acting on the serotonergic system, including 5-HT6 receptors, can diminish habitual and repetitive behaviors associated with clinical syndromes such as obsessive-compulsive disorder, and may have implications for addiction as well. To examine the role of 5-HT6 receptors in the acquisition and persistence of habitual behavior, we manipulated 5-HT6 receptor expression in the DLS with herpes simplex virus vectors in combination with different behavioral procedures; control rats received a vector expressing enhanced green fluorescent protein. In one set of experiments, rats were tested under conditions that favor the acquisition of either discrete action–outcome responding or repetitive responding; increased 5-HT6 receptor expression in DLS did not alter learning in either paradigm. In the next experiment, rats were over-trained on fixed- then variable-interval schedules, resulting in an escalation of lever pressing over sessions far in excess of that necessary to receive sucrose pellets. After training, rats received viral vector infusion into the DLS. Subsequently, half of each group underwent an omission contingency training session in which they received reinforcement for refraining from pressing the lever, while the other half served as yoked controls. A probe session under extinction conditions was performed the following day. Only rats that received both the 5-HT6 vector and omission contingency training showed reduced lever pressing during the probe session. These results suggest that increasing 5-HT6 receptor signaling in the DLS facilitates behavioral flexibility in the face of changing contingencies.