The sarcoplasmic reticulum (SR) plays a central role in the contraction and relaxation coupling in the myocardium. The SR Ca(2+)-ATPase (SERCA2) transports Ca(2+) inside the SR lumen during relaxation of the cardiac myocyte. It is well known that diminished contractility of the hypertrophic cardiac myocyte is the main factor of ventricular dysfunction in the failing heart. A key feature of the failing heart is a decreased content and activity of SERCA2, which is the cause of some of the physiological defects observed in the hypertrophic cardiomyocyte performance that are important during transition of compensated hypertrophy to heart failure. In this review different possible mechanisms responsible for decreased transcriptional regulation of the SERCA2 gene are examined, which appear to be the primary cause for decreased SERCA2 expression in heart failure. The experimental evidence suggests that several signalling pathways are involved in the downregulation of SERCA2 expression in the hypertrophic and failing cardiomyocyte. Therapeutic upregulation of SERCA2 expression using replication deficient adenoviral expression vectors, pharmacological interventions using thyroid hormone analogues, beta-adrenergic receptor antagonists, and novel metabolically active compounds are currently under investigation for the treatment of uncompensated cardiac hypertrophy and heart failure.