The peptidic neurotransmitter neuropeptide Y (NPY) has been functionally implicated in feeding behavior, cardiovascular regulation, control of neuroendocrine axes, affective disorders, seizures, and memory retention. At least five different receptors mediate NPY actions. In particular, the Y1 receptor appears to be involved in a variety of NPY-induced pathways. This review summarizes the main findings resulting from the use of mice lacking NPY Y1 receptor expression. Interestingly, the overall phenotype of Y1 knockouts mimics metabolic syndrome, which is characterized by obesity, a prediabetic state, and a susceptibility to develop hypertension.