Although it is generally agreed upon that a physically active lifestyle and regular exercise are good for heart health, it is much less appreciated by the public that the prolonged hours of sedentary time resulting from sitting at work or screen time are also risk factors for cardiovascular outcomes and other cardiometabolic diseases. In this short narrative review, evidence is discussed and prudent recommendations are made in the context of the sedentary, affluent lifestyle that characterizes a large proportion of our population. It has become overwhelmingly clear that a sedentary lifestyle is a powerful risk factor for cardiovascular and other chronic diseases. In addition, vigorous physical activity and exercise is also associated with metabolic and cardiovascular adaptations that are compatible with cardiovascular health. In that regard, cardiorespiratory fitness, a reliable metric to assess the ability of the cardiovascular system to sustain prolonged physical work, has been shown to be the most powerful predictor of mortality and morbidity, way beyond classical cardiovascular disease (CVD) risk factors such as smoking, cholesterol, hypertension, and diabetes. On the basis of the evidence available, it is proposed that both dimensions of overall physical activity level (reducing sedentary time and performing regular physical activity or endurance type exercise) should be targeted to reduce CVD risk. Finally, because of the robust evidence that poor cardiorespiratory fitness is an independent risk factor for CVD and related mortality, it is proposed that this simple physiological metric should be incorporated as a vital sign in CVD risk factor evaluation and management.