Neuropeptide Y (NPY), a peptide abundantly expressed in the mammalian nervous system, has been extensively studied using traditional pharmacological and behavioral models. Central administration of NPY or synthetic ligands for its receptors has indicated a role of NPY in anxiety-related behaviors, feeding, regulation of blood pressure, circadian rhythm and other functions. Some limitations inherent in pharmacological approaches, such as lack of selectivity of receptor antagonists, can be elegantly circumvented using genetically modified animals. For NPY, mice lacking NPY, the Y1, the Y2 or the Y5 receptors have been generated. In addition, both mice and rats overexpressing NPY in the central nervous system are available. Here, we review the research carried out so far in the NPY-field using genetically modified animals. Together, these models indicate that stress-related behaviors and regulation of voluntary alcohol intake perhaps are among the most important functions of central NPY, and may provide attractive targets for developing novel therapies in depression, anxiety disorders and alcohol dependence.