The P-type family of ion-transporting ATPases includes all of the isoforms of Na(+)-K(+)-adenosinetriphosphatase (ATPase), the plasma membrane and organellar Ca(2+)-ATPases, gastric H(+)-K(+)-ATPase, and the recently characterized nongastric H(+)-K(+)-ATPases, among others. In epithelial cells, members of this pump family generate the cation gradients responsible for vectorial fluid and solute transport. To carry out this function, each P-type ATPase must be restricted to a specific membrane domain. Newly synthesized ion pumps must be sorted to their appropriate destinations and retained there after their delivery. Recently, progress has been made toward understanding the signals and targeting pathways that epithelial cells employ to generate anisotropic pump distributions. The mechanisms involved in generating these pump distributions may serve as well to regulate pump function.