OBJECTIVES:  Cardiovascular disease (CVD) mortality has decreased by >60% over the past 50 years, partially due to development of preventive therapeutics (e.g., statins, antihypertensive agents) and acute interventions, however progress is slowing. With an aging US population, an expected rise in obesity and diabetes, and competing needs for limited resources, future patterns of CVD are uncertain. METHODS:  We developed a Microsoft® Excel-based model to project trends in CVD mortality. National Health and Nutrition Examination Survey (NHANES) data was used to estimate population-level trends in CVD-related risk factors (e.g., smoking, diabetes, cholesterol, blood pressure). Cohorts of 1,000,000 individuals were generated and assigned characteristics based on risk factor projections. Microsimulations were performed to estimate the 10-year CVD risk for individuals using the Framingham Risk Score. Risk scores, calculated separately for men and women, were used to predict future CVD prevalence and mortality. Scenarios, differing by uptake of current therapies, pharmaceutical innovations with efficacy exceeding available alternatives, and risk factor prevalence, were assessed to estimate the annual mortality rate from 2017-2040 given uncertainty. RESULTS:  When incorporating a demographic shift, but assuming constant risk factors, current treatment utilization, and no major innovations, we predicted the CVD mortality rate would increase by 12% by 2040. In order to decrease CVD mortality by 15% given projected changes in risk factors, innovative therapies that can provide incremental benefits equal to or greater than the those associated with the introduction of statins will need to be identified and widely utilized. CONCLUSIONS:  Although CVD is the leading area of direct healthcare costs with <$230 billion spent in 2013, further investment is necessary to continue reducing the CVD burden. Increasing access and adherence to current preventative therapeutics could slow the increase in mortality, but innovative therapies may be needed to maintain the downward trend in CVD deaths.