The peptide galanin has been implicated in the neuroendocrine regulation of reproduction and energy balance. To gain more insight into the functional significance of galanin in these processes, we studied the phenotype of mice that either overexpress galanin in the brain under the control of the dopamine β-hydroxylase promoter (GALTG) or have a complete absence of galanin expression (GALKO). Both GALTGs and GALKOs had body weights and feeding patterns that were indistinguishable from wild-type (WT) control animals, and both genotypes were reproductively competent. Serum levels of follicle-stimulating hormone were significantly higher in GALKOs and slightly lower in GALTGs than in their respective WT controls. Both GALTGs and GALKOs showed a normal response to fasting, but when GALKO mice were treated with leptin during fasting, levels of corticosterone and testosterone were altered compared to WT mice. In addition, GALKOs were more sensitive than WT controls to the effects of chronic leptin treatment on body weight and fat pad mass, whereas GALTGs showed responses to this metabolic challenge that were indistinguishable from their controls. When galanin was administered centrally, GALKOs had lower testosterone and corticosterone levels than did WT mice. These results suggest that the complete loss of galanin leads to significant alterations in neuroendocrine homeostasis, whereas targeted overexpression of galanin in the brain does not interfere with normal neuroendocrine function.