In modern society, suicide is a major public health problem, yet currently the neurobiologic risk factors associated with suicide are still poorly understood. Recent studies demonstrate that alteration in synaptic and structural plasticity is key to affective disorders and suicide. Signal transduction molecules play an important role in such plastic events. Protein kinase A (PKA) is one of the crucial signaling molecules that, by phosphorylating proteins, affects a wide array of physiologic functions in the brain. This article focuses on recent findings that indicate alterations in activation and expression of PKA may be involved in the pathophysiology of suicide. The authors critically discuss these findings in human postmortem brain and in pre-clinical models as well as attempt to elucidate how stress, one of the major risk factors in suicide, may be crucial in altering PKA. In addition, the functional significance of altered PKA in respect to its target molecules cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor is also discussed. These findings provide a better understanding of the neurobiology of suicide and indicate that altered PKA may be one of the important neurobiologic risk factors associated with suicide.