The kidney is an important regulatory organ responsible for maintaining constant blood volume and composition despite wide variations in the intake of food and water. Throughout the nephron, the functional unit of the kidney, there is a wide variety of proteins that function to add additional waste products and to recover needed materials from the lumen filtrate. The collecting duct of the nephron is the primary renal location for the H⁺, K⁺-ATPases, a group of ion pumps that function in both acid/base balance and potassium homeostasis. This review summarizes the present understanding of the structure and functions for the different subtypes of the H⁺, K⁺-ATPases under specific physiologic conditions. The obstacles in determining the pharmacologic properties of the different subtypes are considered and future directions for the inhibition and/or stimulation of the H+, K+-ATPases are evaluated.