The Na⁺‐Ca²⁺ exchanger (NCX) on the plasma membrane is thought to be the main calcium extrusion system from the cytosol to the extracellular space in many mammalian excitable cells, including cardiac myocytes. However, the pathophysiological role of NCX in the heart is still unclear because of the lack of known specific inhibitors of NCX. To determine the role of NCX in cardiac contraction and the development of cardiac hypertrophy, we imposed pressure overload on the heart of heterozygous NCX knockout (KO) mice by constricting transverse aorta, and examined cardiac function and morphology 3 wk after operation. Although there was no difference in cardiac function between sham‐operated KO mice and sham‐operated wild‐type (WT) mice, KO mice showed higher left ventricular pressure and better systolic function than WT mice in response to pressure overload. Northern blot analysis revealed that mRNA levels of sarcoplasmic reticulum Ca²⁺‐ATPase were reduced by pressure overload in left ventricles of WT but not of KO mice. However, hypertrophic changes with interstitial fibrosis were more prominent in KO mice than WT mice. These results suggest that reduction of NCX results in supernormalized cardiac function and causes marked cardiac hypertrophy in response to pressure overload.—Takimoto, E., Yao, A., Toko, H., Takano, H., Shimoyama, M., Sonoda, M., Wakimoto, K., Takahashi, T., Akazawa, H., Mizukami, M., Nagai, T., Nagai, R., Komuro, I. Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload. FASEB J. 16, 373–378 (2002)