When ATP is released as a neurotransmitter from central and peripheral nerves it acts at P2X purinoceptors to produce postsynaptic depolarization and excitation. The P2X purinoceptor was originally classified on the basis of the relative agonist potencies of ATP and a number of its structural analogues. However, it is now clear that the potency of some agonists is greatly decreased by breakdown by ectonucleotidase enzymes, leading to an incorrect determination of agonist potency order. In this article, Charles Kennedy and Paul Leff discuss recent results that indicate that the established classification of P2X purinoceptors is no longer valid and needs redefinition.