During the past two decades, several cell membrane receptors, which preferentially bind extracellular nucleotides, and their analogs have been identified. These receptors, collectively known as nucleotide receptors or “purinergic” receptors, have been characterized and classified on the basis of their biological actions, their pharmacology, their molecular biology, and their tissue and cell distribution. For these receptors to have biological and physiological relevance, nucleotides must be released from cells. The field of extracellular ATP release and signaling is exploding, as assays to detect this biological process increase in number and ingenuity. Studies of ATP release have revealed a myriad of roles in local regulatory (autocrine or paracrine) processes in almost every tissue in the body. The regulatory mechanisms that these receptors control or modulate have physiological and pathophysiological roles and potential therapeutic applications. Only recently, however, have ATP release and nucleotide receptors been identified along the renal epithelium of the nephron. This work has set the stage for the study of their physiological and pathophysiological roles in the kidney. This review provides a comprehensive presentation of these issues, with a focus on the renal epithelium.