In light of the recently issued guidelines of the Fourth Joint Task Force of the European Society of Cardiology and Other Societies on CVD Prevention in Clinical Practice and of the Systematic COronary Risk Evaluation (SCORE) cardiovascular disease risk estimation charts, this review discusses the risk factor concept in relation to the prevention of cardiovascular disease in clinical practice, in particular in relation to atherosclerosis and its clinical manifestations such as angina pectoris, myocardial infarction, transient ischemic attacks, and ischemic stroke. Special attention is given to modifiable risk factors such as smoking, sedentariness, nutritional imbalance, impaired glucose tolerance and diabetes, blood pressure elevation, dyslipidemia, overweight and abdominal adiposity, and markers of chronic inflammation. Other emerging risk factors are gaining increasing importance in contributing to the estimation of total cardiovascular (CV) risk. These include heart rate, socioeconomic status, and gender. The latter are of great importance in helping the clinician tailor preventive strategies to individual patients. The estimated total CV risk should be handled as a continuum and not in a dichotomous way. The higher a patient’s total CV risk, the more aggressively should CVD prevention be implemented...