© 2016 S. Karger AG, Basel. Suicide is a major public concern. About one million people commit suicide every year worldwide. In the teenage population, it is the third leading cause of death in the USA. Although the underlying pathophysiology of suicide is not very well understood, postmortem brain studies have provided a greater understanding of the neurobiological abnormalities associated with suicide. This chapter discusses the role of neurotransmitter systems, particularly the serotonergic and noradrenergic systems, in suicidal behavior. Since these neurotransmitters mediate their functional responses by activating intracellular signaling pathways, a detailed account of changes in receptor signaling has been discussed. Major emphasis has been given to the phosphoinositide and adenylyl cyclase-cyclic adenosine monophosphate signaling pathways as these signaling components have been shown to be activated by both the serotonergic and noradrenergic pathways. More specifically, the role of GTP binding proteins and downstream effector molecules protein kinase C and protein kinase A and the regulation of target gene brain-derived neurotrophic factor have been discussed. Altogether, these studies provide a comprehensive knowledge of neurobiological abnormalities associated with suicide and provide vulnerability factors that may predispose a person to suicidal behavior.