Purinergic neurotransmission was proposed in 1972 following identification of adenosine 5'-triphosphate (ATP) as the transmitter in non-adrenergic, non-cholinergic inhibitory nerves in guinea-pig taenia coli. Subsequently ATP was identified as a co-transmitter in sympathetic, parasympathetic and most nerves in the peripheral and central nervous systems. ATP acts as a short-term signalling molecule in neurotransmission, neuromodulation and secretion and has long-term (trophic) roles in cell proliferation, differentiation and death in development and regeneration. Three subclasses of purine and pyrimidine receptors have been identified, P1 adenosine receptors (4 subtypes), P2X ionotropic nucleotide receptors (7 subtypes) and P2Y metabotropic receptors (8 subtypes). ATP is released physiologically by many cell types by mechanical deformation and, after release, ATP undergoes ectonucleotidase degradation. Purinergic receptors appeared early in evolution and have a widespread distribution on many non-neuronal cells and neurons. Purinergic signalling is involved in embryonic and stem cell development. There is a rapidly growing literature about the pathophysiology of purinergic signalling including therapeutic developments for diseases, including stroke, thrombosis, osteoporosis, kidney failure, bladder incontinence, cystic fibrosis, dry eye, cancer and brain disorders.