AbstractThe concept of purinergic neurotransmission was proposed in 1972, after it was shown that adenosine 5′‐triphosphate (ATP) was a transmitter in non‐adrenergic, non‐cholinergic inhibitory nerves in the guinea pig taenia coli. Subsequently, ATP was identified as a cotransmitter in sympathetic and parasympathetic nerves, and it is now recognized that ATP acts as a cotransmitter in most nerves in both the peripheral nervous system and central nervous system (CNS). ATP acts as a fast excitatory neurotransmitter or neuromodulator and has potent long‐term (trophic) roles in cell proliferation, differentiation, and death in development and regeneration, as well as in disease. Three subclasses of receptors to purines and pyrimidines have been identified, P1 adenosine receptors (with four subtypes), P2X ionotropic nucleotide receptors (seven subtypes), and P2Y metabotropic nucleotide receptors (eight subtypes). ATP is released physiologically by many different cell types by mechanical deformation, and after release ATP undergoes rapid enzymatic degradation by ectonucleotidases. Purinergic receptors appeared early in evolution and have a widespread distribution on many different non‐neuronal cell types as well as neurons. There is evidence for the involvement of purinergic signaling in embryonic development and in the activities of stem cells. There is a rapidly growing literature about the pathophysiology of purinergic signaling, and there are therapeutic developments for a variety of diseases, including stroke and thrombosis, osteoporosis, kidney failure, bladder incontinence, cystic fibrosis, dry eye, cancer, and disorders of the CNS, such as Alzheimer's, Parkinson's, and Huntington's disease, multiple sclerosis, epilepsy, migraine, and neuropsychiatric disorders.WIREs Membr Transp Signal2012, 1:116–125. doi: 10.1002/wmts.14For further resources related to this article, please visit theWIREs website.