Overexpression of the cardiac Na+-Ca2+ exchanger may play an important role in pathological conditions like hypertrophy and heart failure. To investigate the contribution of enhanced Na+-Ca2+ exchange to intracellular Ca2+ handling both under physiological as well as pathological conditions, we have generated a transgenic mouse overexpressing the canine cardiac Na+-Ca2+ exchanger. In transgenic mouse myocytes, the exchanger contributed significantly to the onset and decay of contraction and was able to compensate for impaired SR Ca2+ handling. Under appropriate conditions enhanced Na+-Ca2+ exchange may support development of an intracellular Ca2+ transient and induce contraction. Na+-Ca2+ exchange may be an important Ca2+ transport mechanism in myocardial dysfunction like heart failure, for which impaired SR function has been postulated. Nevertheless, studies on the transgenic mouse model also provide evidence that under pathological conditions such as ischemia/reperfusion, increased SR Ca2+ content, or increased hemodynamic load, overexpressed Na+-Ca2+ exchange activity may compromise contractile performance and lead to hypertrophy and heart failure.