Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of ␣42 receptors, and in equilibrium binding assays, it is highly selective for the ␣42 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at ␣42 receptors, with an EC 50 of 2.3 Ϯ 0.3 M and an efficacy (relative to acetylcholine) of 13.4 Ϯ 0.4%. Varenicline has lower potency and higher efficacy at ␣34 receptors, with an EC 50 of 55 Ϯ 8 M and an efficacy of 75 Ϯ 6%. Varenicline also seems to be a weak partial agonist at ␣32 and ␣6-containing receptors, with an efficacy Ͻ10%. It is remarkable that varenicline is a potent, full agonist at ␣7 receptors with an EC 50 of 18 Ϯ 6 M and an efficacy of 93 Ϯ 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric ␣7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.