Cardiovascular disease (CVD) remains the major cause of total mortality in Europe. Important inequalities are evident in that CVD deaths account for more than 50% of all deaths in some countries, compared with less than 30% in others. An important indicator of the burden of CVD morbidity is the hospitalization rate for cardiovascular conditions, which is 30% higher in men than in women, in particular for acute myocardial infarction admissions, although across the lifespan CVD is an equal opportunity disease. Global risk calculation has been considered the best tool for comprehensive cardiovascular primary prevention, to deal with the risk of developing atherosclerotic CVD. Guidelines highlight the importance of identifying asymptomatic patients who would be candidates for more intensive, evidence-based medical interventions that reduce CVD risk. Challenges in cardiovascular risk estimation efforts have included how to estimate risk in vulnerable groups more accurately, such as children and adolescents, young adults, older adults, and immigrants, and how other factors, such as social status or literacy, may influence expected outcomes. The nurse or nurse specialist is uniquely well placed to play a pivotal role in risk estimation and management. Prevention of CVD should take a multidisciplinary, multifactorial, and societal approach including strategies to improve health literacy, empowerment, self-care management, and environmental adaptations. Nurses must take an active part in reducing the burden of CVD through these strategies.