Fatty liver is an increasingly prevalent condition that is associated with several metabolic derangements, thus necessitating the development of effective therapeutic interventions. Growing evidence from cross-sectional studies suggest that physical activity may be a promising therapy for fatty liver. Unfortunately, longitudinal evidence supporting this observation in humans is sparse, as the majority of intervention studies have examined the relationship between liver fat and physical activity in conjunction with caloric and dietary fat restriction. Studies in rats demonstrate a beneficial effect of exercise on liver fat, mainly in situations of high fat feeding or obesity. Thus, the independent contribution of physical activity on variations in liver fat is unknown, but remains a promising intervention that requires further investigation. There is some evidence to suggest that both physical activity and liver fat are independent correlates of cardiovascular and type 2 diabetes risk. The relative contribution of each remains unclear, but implies that both should be considered when developing therapeutic interventions for chronic metabolic disease.