Although the mechanisms underlying most aspects of excitation-contraction (EC) coupling in skeletal muscle are well understood, a very basic step, that of communication between the transverse tubule (TT) region of the plasmalemma and the terminal cisternae of the sarcoplasmic reticulum (SR), has not been elucidated. Several types of TT to SR communication have been proposed, including electrical, chemical, and mechanical coupling. Current evidence supports a combination of the latter two. Studies of single rabbit skeletal muscle fibers, skinned by peeling the sarcolemma, demonstrate that a chemical stimulus for SR Ca2+release, inositol trisphosphate (InsP3), could play a role in skeletal EC coupling. InsP3appears to open the same SR Ca2+channel that is activated by caffeine, Ca2+, and depolarization of TTs; all of these stimuli are inhibited by the SR Ca2+channel blocker ruthenium red.