Spent mushroom substrate (SMS) is the residual biomass generated after harvesting the fruitbodies of edible/medicinal fungi. Disposal of SMS, the main by-product of the mushroom cultivation process, often leads to serious environmental problems and is financially demanding. Efficient recycling and valorization of SMS are crucial for the sustainable development of the mushroom industry in the frame of the circular economy principles. The physical properties and chemical composition of SMS are a solid fundament for developing several applications, and recent literature shows an increasing research interest in exploiting that inherent potential. This review provides a thorough outlook on SMS exploitation possibilities and discusses critically recent findings related to specific applications in plant and mushroom cultivation, animal husbandry, and recovery of enzymes and bioactive compounds.