Cardiovascular disease (CVD) is the most important cause of premature death and disability globally. Much is known of the main aetiological risk factors, including elevated blood pressure, dyslipidaemia and smoking, with a raft of additional risks of increasing prevalence, such as obesity and diabetes. Furthermore, some of the most secure evidence-based management strategies in healthcare relate to interventions that modify risk. Yet major gaps remain in the implementation of such evidence, summarized in international guideline recommendations. Some of this gap relates to knowledge deficits amongst clinicians, but also to continued uncertainties over interpretation of the evidence base and areas where data are less available. This article collection in BMC Medicine seeks to offer reflections in each of these areas of uncertainty, spanning issues of better diagnosis, areas of controversy and glimpses of potentially potent future interventions in the prevention of CVD.