Sestrins are a family of stress-inducible proteins that are critical for stress adaptation and the maintenance of metabolic homeostasis. High expression of Sestrins is observed in skeletal and cardiac muscle tissues, suggesting their significance in the physiological homeostasis of these organs. Furthermore, expression of Sestrins is dynamically controlled in the tissues, based on the level of physical activity and the presence or absence of stress insults. Genetic studies in model organisms have shown that muscular Sestrin expression is critical for metabolic homeostasis, exercise adaptation, stress resistance, and repair and may mediate the beneficial effects of some available therapeutics. The current minireview summarizes and discusses recent findings that shed light on the role of Sestrins in regulating muscle physiology and homeostasis.