Four decades ago, Iran encountered rapid sociodemographic and economic transitions. This review was carried out to investigate the trend of cardiovascular disease (CVD) prevalence, mortality and morbidity, relevant challenges and suggestions for prevention of CVD. In Iran, the most prevalent causes of death have transited from infectious and diarrheal diseases in 1960 to CVD few decades ago. CVD was the first leading cause of mortality and a million disability adjusted life years (DALYs) led to 46% of all deaths and 20%-23% of the burden of disease in Iran. Ischemic heart disease and stroke are considered the first and second cause of death and DALYs in Iran, respectively. CVD rising epidemic might be related to socioeconomic and cultural changes, nutrition transition, inadequate physical activity, industrialization and urbanization and increasing life expectancy, increasing metabolic and physical risk factors, low accessibility and affordability to primary care and treatment, and low compliance because of economic and psychological problems. Thus, planning and implementing strategies for prevention and control of the disease and its risk factors are on top of the ministry of health agenda in the recent years. Health promotion strategies to prevent and control CVD risk factors, early detection of the disease and treatment of acute and chronic CVD events are essential elements for reducing the burden of CVD in Iran.