Intracellular Ca²⁺ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca²⁺ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca²⁺ entry (SOCE), a Ca²⁺-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca²⁺ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca²⁺ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca²⁺-permeable channel located on transverse tubules. It is commonly accepted that Ca²⁺ entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca²⁺ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential.