The neuropeptide galanin and its three receptors are widely distributed throughout the mammalian brain, with highest levels in limbic brain nuclei. Galanin is co-localized with classical neurotransmitters, including acetylcholine and the monoamines serotonin and noradrenaline. Behaviorally, the galaninergic system regulates numerous cognitive and affective behaviors that are essential for normal homeostasis. Recently, a large body of preclinical evidence suggests that galanin and its receptors represent putative targets for the development of novel anxiolytic and antidepressant drugs, which we describe in detail in the current review. Studies of galanin receptor knockout mice indicate a role for both the galanin receptor type 1 (GalR1) and GalR2 in mouse models of anxiety. We have previously demonstrated that levels of galanin mRNA are increased in limbic brain nuclei after different modalities of antidepressant treatment in rats, whereas the behavioral effects of a subchronic selective serotonin reuptake inhibitor can be reversed by the galanin receptor antagonist M40. Furthermore, the systemically active GalR1/GalR2 agonists, galnon and galmic, display antidepressant-like effects in the rat forced swim test. Initial results with a selective GalR3 antagonist indicate similar antidepressant-like effects in both rat and mouse preclinical screens. These promising results warrant further study of the galaninergic system as a novel substrate for the development of both anxiolytic and antidepressant drugs. Drug Dev. Res. 65:227–236, 2005. © 2005 Wiley-Liss, Inc.