Mitochondria Na(+)-Ca(2+) exchange (NCX(mit)) was first discovered by Carafoli et al. in 1974. Thereafter, the mechanisms and roles of NCX(mit) have been extensively studied. We review NCX(mit) in cardiomyocytes and lymphocytes by presenting our recent studies on it. Studies of NCX(mit) in rat ventricular cells demonstrated that NCX(mit) is voltage dependent and electrogenic. A targeted knockdown and knockout of NCLX in HL-1 cardiomyocytes and B lymphocytes, respectively, significantly reduced the NCX(mit) activity, indicating that NCLX is a major component of NCX(mit) in these cells. The store-operated Ca(2+) entry was greatly attenuated in NCLX knockout lymphocytes, suggesting that substantial amount of Ca(2+) enters into mitochondria and is released to cytosol via NCX(mit). NCX(mit) or NCLX has pivotal roles in Ca(2+) handling in mitochondria and cytoplasm.