Recent studies of cloned mammalian sodium cotransporters in heterologous systems have revealed that these integral membrane proteins serve multiple functions as cotransporters, uniporters, channels and water transporters. Some progress has been gained in understanding their secondary structure, but information on helical bundling and tertiary structure is lacking. Site-directed mutagenesis and the construction of chimeras have resulted in the identification of residues and domains involved in ligand binding, and natural mutations have also been found that are responsible for human genetic diseases. Major factors in the short-term regulations of cotransporter function by protein kinases are exocytosis and endocytosis.