Clinical trials have been instrumental in reducing the morbidity and mortality associated with cardiovascular disease, especially in the developed world. Recently however this improvement has plateaued, highlighting the importance of optimising current strategies and considering alternative practises. Inequalities in global healthcare, the changing patient profile as a result of an obesity and diabetes epidemic, and inadequate utilisation of evidence-based treatments are partly responsible. Despite pharmacotherapies such as statins having substantial evidence for cardiovascular benefit, patient response may be variable with genetic factors thought to be partly responsible. Although randomised controlled trials remain the backbone of clinical research, they have limitations including time taken to complete a trial and the financial costs associated with it. In this opinion-based paper, we discuss some of the key considerations for the future of cardiovascular disease prevention.