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The sarcoplasmic reticulum of skeletal muscle cells is a highly ordered structure consisting of an intricate network of tubules and cisternae specialized for regulating Ca²⁺ homeostasis in the context of muscle contraction. The sarcoplasmic reticulum contains several proteins, some of which support Ca²⁺ storage and release, while others regulate the formation and maintenance of this highly convoluted organelle and mediate the interaction with other components of the muscle fiber. In this review, some of the main issues concerning the biology of the sarcoplasmic reticulum will be described and discussed; particular attention will be addressed to the structure and function of the two domains of the sarcoplasmic reticulum supporting the excitation–contraction coupling and Ca²⁺-uptake mechanisms.