Carbohydrate is a crucial energy fuel for exercise, and carbohydrate supplementation as peri-exercise has beneficial effects on exercise performance. However, recent studies have indicated the possibility that periodized carbohydrate restriction improves exercise performance. Carbohydrate restriction before exercise increases fatty-acid oxidation (FAO) and alternatively prevents carbohydrate consumption during exercise. This may contribute to the prevention of muscle glycogen depletion during endurance exercise competition. Additionally, acute and chronic studies have shown that peri-exercise carbohydrate restriction enhances molecular and functional adaptation related to FAO. Similarly, exercise training in a low-muscle glycogen state accompanied by carbohydrate restriction was reported to enhance mitochondrial biogenesis and improve FAO capacity, aerobic capacity, and endurance performance in untrained and highly trained subjects. The potential mechanism of these metabolic adaptations may be related to elevated circulating fatty-acid and adrenaline concentration during exercise with carbohydrate restriction and/or a low-muscle glycogen state. In addition, a decrease in muscle glycogen content may trigger signaling pathways related to FAO and mitochondria biogenesis by activating proteins with a glycogen-binding domain. This article reviews the effects of exercise with carbohydrate restriction and/or low-muscle glycogen state on metabolic adaptation and exercise performance and describes the molecular mechanisms and availability.