Abstract: Skeletal muscle is the largest single organ of the body. Skeletal muscle damage may lead to loss of muscle function, and widespread muscle damage may have serious systemic implications due to leakage of intracellular constituents to the circulation. Ca²⁺ acts as a second messenger in all muscle and may activate a whole range of processes ranging from activation of contraction to degradation of the muscle cell. It is therefore of vital importance for the muscle cell to control [Ca²⁺] in the cytoplasm ([Ca²⁺]_c). If the permeability of the sarcolemma for Ca²⁺ is increased, the muscle cell may suffer Ca²⁺ overload, defined as an inability to control [Ca²⁺]_c. This could lead to the activation of calpains, resulting in proteolysis of cellular constituents, activation of phospholipase A₂ (PLA₂), affecting membrane integrity, an increased production of reactive oxygen species (ROS), causing lipid peroxidation, and possibly mitochondrial Ca²⁺ overload, all of which may further worsen the damage in a self‐reinforcing process. An increased influx of Ca²⁺ leading to Ca²⁺ overload in muscle may occur in a range of situations such as exercise, mechanical and electrical trauma, prolonged ischemia, Duchenne muscular dystrophy, and cachexia. Counteractions include membrane stabilizing agents, Ca²⁺ channel blockers, calpain inhibitors, PLA₂ inhibitors, and ROS scavengers.