Obesity has become one of the main risk factors threatening human health, and it is the core cause of various major chronic diseases. Although the efficacy of exercise intervention on obesity remains controversial, it has long been considered one of the most effective and safest approach for managing obesity and providing benefits to patients with obesity. Metabolic flexibility, especially skeletal muscle metabolic flexibility, has a profound impact on exercise weight loss due to its association with muscle fiber types. To understand the effect of exercise intervention on obese individuals with different muscle types, this review emphasizes high calorie diet induced obesity, investigates the interrelationships among obesity, exercise, and metabolic flexibility, and identifies potential molecular targets within this framework to inform future combined therapeutic strategies targeting metabolic inflexibility.  Kulcsszavak obesity, exercise, metabolic flexibility, molecular mechanism, molecular target