Cardiolipin, a lipid crucial for the preservation of mitochondrial function, undergoes perpetual remodeling to adapt to the fluctuating energy requirements of organs and tissues under both physiological and pathological states. A reduction in cardiolipin levels has been linked to the pathogenesis of a multitude of diseases, encompassing cardiomyopathy, Parkinson’s disease, and age-related sarcopenia. Notably, physical exercise has been shown to enhance cardiolipin levels across various tissues, thereby fortifying the body's defense against the detrimental effects of a spectrum of chronic diseases on overall health. In this review, we explore recent advancements in understanding cardiolipin remodeling in response to both exercise and disease states, elucidating the interplay between mitochondrial biogenesis and cardiolipin biosynthesis in orchestrating mitochondrial function, thereby facilitating adaptations to the metabolic demands posed by physical activity and pathological conditions.