The concept that adenine and uridine nucleotides function as extracellular signaling molecules has been markedly expanded in the last decade. At least 15 nucleotide-activated cell surface receptors exist, and remarkably broad and varied physiological responses are known to occur downstream of nucleotide receptor activation. The significance of nucleotides as extracellular molecules also is underscored by ubiquitous distribution of several large classes of ectoenzymes that catalyze nucleotide breakdown and interconversion. Purinergic signaling was initially proposed on the basis of smooth muscle responses to autonomic nerve stimulation that were not blocked by adrenergic receptor antagonists (Burnstock, 1972; Burnstock, 1978; Burnstock and Kennedy, 1985). However, observation of responses to nucleotides in essentially all peripheral tissues including those not significantly innervated by the autonomic nervous system indicates that extracellular nucleotides arising from non-neuronal source underlie many important physiological processes (Ralevic and Burnstock, 1998). This Minireview focuses briefly on the receptors and ectoenzymes that mediate and terminate the action of extracellular nucleotides (Fig. 1) and summarizes the evidence regarding neuroendocrine secretion of ATP. We then consider in some detail current understanding of nucleotide release from nonexcitable tissues.