The distal tubule of the mammalian kidney, defined as the region between the macula densa and the collecting duct, is morphologically and functionally heterogeneous. This heterogeneity has stymied attempts to define functional properties of individual cell types and has led to controversy concerning mechanisms and regulation of ion transport. Recently, molecular techniques have been used to identify and localize ion transport pathways along the distal tubule and to identify human diseases that result from abnormal distal tubule function. Results of these studies have clarified the roles of individual distal cell types. They suggest that the basic molecular architecture of the distal nephron is surprisingly similar in mammalian species investigated to date. The results have also reemphasized the role played by the distal tubule in regulating urinary potassium excretion. They have clarified how both peptide and steroid hormones, including aldosterone and estrogen, regulate ion transport by distal convoluted tubule cells. Furthermore, they highlight the central role that the distal tubule plays in systemic calcium homeostasis. Disorders of distal nephron function, such as Gitelman's syndrome, nephrolithiasis, and adaptation to diuretic drug administration, emphasize the importance of this relatively short nephron segment to human physiology. This review integrates molecular and functional results to provide a contemporary picture of distal tubule function in mammals.