© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany. All rights reserved. Neuropeptides, protein-like molecules used for direct communication between neurons, may play a critical role in the pathophysiology of mood disorders and suicidal behavior. This chapter aims to critically review the current literature on associations between neuropeptides, major affective disorders, and suicidal behavior. Most studies included in this overview reported an association between suicidality and corticotropin-releasing factor (CRF), VGF nerve growth factor inducible (VGF), cholecystokinin (CCK), orexin, substance P, and neuropeptide Y (NPY). It has been suggested that these molecules play a key role in many biological functions and act as important neuromodulators of emotional processing. The majority of the studies reviewed in this chapter found that suicidal subjects display higher mean concentrations of various neuropeptides compared to control subjects although depressed patients and suicide completers may also display lower NPY levels throughout the brain compared to healthy controls or individuals deceased from causes other than suicide. In addition, some studies have reported that orexin and corticotropin-releasing hormone (CRH) levels are lower in suicidal patients. In spite of these cross-sectional reports, a causal link between neuropeptide dysregulation and suicidality cannot be determined. The main implications of the studies that are included in the present chapter are critically analyzed and discussed.