A healthy lifestyle is composed primarily of regular structured physical activity (i.e., exercise). As a result, there is vast research into the clinical benefits of exercise, in most cases showing a better effect than drug interventions. Current physical activity guidelines from the American College of Sports Medicine recommend a minimum of 150 minutes of moderate-intensity exercise, or 75 minutes of high-intensity exercise, per week to maintain and improve fitness and to reduce the risk of noncommunicable diseases (e.g., type 2 diabetes, cancer, osteoporosis, stroke and others). This research aimed to compare the effects of moderate- versus high-intensity exercise on fitness, vascular health, body composition, blood pressure, cholesterol, long-term glucose metabolism and inflammation in healthy and diseased populations (i.e., obesity, cardiac rehabilitation, metabolic syndrome and type 2 diabetes). Overall, we found that high-intensity exercise was more effective than moderate intensity in improving fitness and vascular health. Moderate-intensity exercise, however, was more effective than high-intensity in improving long-term glucose metabolism. No differences between high- and moderate-intensity exercise were found in the adaptations of body composition, blood pressure, cholesterol and inflammation. In the process of individualized training prescription, health-enhancing effects of exercise training may be boosted by considering individual characteristics, and – most importantly – the target endpoint.