The comparison of cardiac and skeletal muscle structure reveals differences which can be related to differences in the functional characteristics of the two muscle types. Examples which are discussed include the sarcolemma, transverse tubules and sarcoplasmic reticulum which serve as major sources of contraction-dependent calcium. Mechanisms by which calcium is made available to, and utilized by the myofibrils is discussed in relation to the mechanics of muscle contraction as a basis for the discussion of excitation-contraction coupling in cardiac and skeletal muscle. Excitation-contraction coupling in skeletal muscle is considered to be mediated by a voltage-dependent charge movement within the region of the sarcolemma (T-tubule): junctional sarcoplasmic reticulum. Depolarization of the sarcolemma initiates the charge movement which may result in a change in sarcoplasmic reticulum membrane potential and ion conductance which is associated with release of calcium to the myofibrils. In cardiac muscle, excitation appears to be linked to contraction by a different although not mutually exclusive mechanism, ie, by a process of calcium induced-calcium release. Depolarization of the cardiac sarcolemma is associated with an influx of calcium into the cell which initiates the release of more calcium from the sarcoplasmic reticulum to activate the myofibrils. One major mechanism that is predominantly active in cardiac muscle to regulate excitation-contraction coupling is the adenylate cyclase-cAMP-protein kinase system. Cyclic AMP-dependent protein kinase mediated phosphorylation of at least three sites within the myocardium have been identified (myofibrils, sarcoplasmic reticulum and sarcolemma) which appear to modulate myocardial function. These sites, which are the primary regulatory sites of calcium and muscle contraction, may be sites of major dysfunction during cardiac disease.