S. R. Houser, V. Piacentino III and J. Weisser. Abnormalities of Calcium Cycling in the Hypertrophied and Failing Heart. Journal of Molecular and Cellular Cardiology (2000) 32, 1595–1607. Progressive deterioration of cardiac contractility is a central feature of congestive heart failure (CHF) in humans. In this report we review those studies that have addressed the idea that alterations of intracellular calcium (Ca²⁺) regulation is primarily responsible for the depressed contractility of the failing heart. The review points out that Ca²⁺transients and contraction are similar in non-failing and failing myocytes at very slow frequencies of stimulation (and other low stress environments). Faster pacing rates, high Ca²⁺and β-adrenergic stimulation reveal large reductions in contractile reserve in failing myocytes. The underlying cellular basis of these defects is then considered. Studies showing changes in the abundance of L-type Ca²⁺channels, Ca²⁺transport proteins [sarcoplasmic reticulum Ca²⁺ATPase (SERCA2), phospholamban (PLB), Na⁺/Ca²⁺exchanger (NCX)] and Ca²⁺release channels (RYR) in excitation–contraction coupling and Ca²⁺release and uptake by the sarcoplasmic reticulum (SR) are reviewed. These observations support our hypotheses that (i) defective Ca²⁺regulation involves multiple molecules and processes, not one molecule, (ii) the initiation and progression of CHF inolves defective Ca²⁺regulation, and (iii) prevention or correction of Ca²⁺regulatory defects in the early stages of cardiac diseases can delay or prevent the onset of CHF.