The Ca2+ ATPase of sarcoplasmic reticulum has a prominent role in excitation/contraction coupling of cardiac muscle, as it induces relaxation by sequestering Ca2+ from the cytoplasm. The stored Ca2+ is in turn released to trigger contraction. We review here experiments demonstrating that in cardiac myocytes Ca2+ signaling and contractile activation are strongly altered by pharmacological inhibition or transcriptional down-regulation of SERCA. On the other hand, kinetics, and intensity of Ca2+ signaling are improved by SERCA overexpression following delivery of exogenous cDNA by adenovirus vectors. Experiments on adrenergic hypertrophy demonstrate SERCA down-regulation, consistent with its pathogenetic involvement in cardiac hypertrophy and failure, as also shown in other experimental models and clinical studies. Compensation by alternate Ca2+ signaling proteins, including functional activation and increased expression of Na+/Ca2+ exchanger and TRPC proteins has been observed. These compensatory mechanisms, including calcineurin activation, remain to be clarified and are a most important subject of current studies. (c) 2007 Elsevier Inc. All rights reserved.