The link between a physically active lifestyle and human health, first described by Hippocrates, was scientifically scrutinized for the last seven decades. The cumulative evidence from large and well-designed epidemiologic studies strongly supports a physically active lifestyle that leads to improved cardiorespiratory fitness (CRF) which confers significant health benefits across the age, gender, and race spectra. The health benefits are evident beyond an exercise volume threshold and increase progressively with higher exercise volumes and are independent of comorbidities. Specifically, increased CRF is strongly and inversely associated with the incidence of chronic cardiometabolic diseases, and the risk of premature mortality. In dyslipidemic populations, CRF is equally effective with statin therapy in lowering mortality risk. However, the combination of the two therapies (CRF and statin treatment) were more effective than either therapy alone. In non-diabetic patients the incidence of diabetes mellitus (T2DM) was amplified by obesity and statins and was attenuated by high CRF. In T2DM patients treated with statins the progression to insulin therapy (worsening of T2DM) was amplified by obesity and statins and was attenuated by high CRF. There is also evidence that excessive amounts of physical activity (work volume) are counterproductive and even harmful. The recommended exercise volume an intensity necessary for health benefits is relatively moderate and achievable by most middle-aged and older individuals engaging in such activities as brisk walk 30–50 min per day most days of the week. Nevertheless, exercise prescriptions should be personalized.