Efforts to examine the relevant mechanisms involved in skeletal muscle fatigue are focusing on Ca²⁺ handling within the active muscle cell. It has been demonstrated time and again that reductions in sarcoplasmic reticulum (SR) Ca²⁺release resulting from increased or intense muscle contraction will compromise tension development. This review seeks to accomplish two related goals: 1) to provide an up-to-date molecular understanding of the Ca²⁺-release process, with considerable attention devoted to the SR Ca²⁺ channel, including its associated proteins and their regulation by endogenous compounds; and2) to examine several putative mechanisms by which cellular alterations resulting from intense and/or prolonged contractile activity will modify SR Ca²⁺ release. The mechanisms that are likely candidates to explain the reductions in SR Ca²⁺ channel function following contractile activity include elevated Ca²⁺ concentrations, alterations in metabolic homeostasis within the “microcompartmentalized” triadic space, and modification by reactive oxygen species.