Na/Ca exchanger (NCX) and plasma membrane Ca2+ ATPase are the Ca2+ efflux mechanisms known in mammalian cells. NCX is the main transporter to efflux intracellular Ca2+ in the heart. NCX protein contains nine putative transmembrane domains and a large intracellular loop joining two sets of the transmembrane domains. The intracellular loop regulates the activity of the NCX by interacting with other proteins and nonprotein factors, such as ions, PIP2. Several proteins that are associated with NCX have been identified recently. Similarly, plasmalemmal Ca2+ ATPase (PMCA) has 10 putative transmembrane domains, and the C-terminal intracellular region inhibits transporter activity. There are several proteins associated with PMCA, and the roles of the associated proteins of PMCA vary from specific localization to involving PMCA in signal transduction. Elucidation of structural and functional roles played by these associated proteins of NCX and PMCA will provide opportunities to develop drugs of potential therapeutic value.