To mark the 10th anniversary of Nature Reviews Cardiology in November 2014, five of our Advisory Board members were invited to consider a topic within cardiology about which we know too little. A diverse range of subjects are highlighted in this Perspectives article, including preoperative assessment of right ventricular function, the burden of cardiomyopathies in Africa, the measurement of fractional flow reserve to guide coronary intervention, the interaction between genes and environment in cardiovascular disease, and the difficulty of predicting atherosclerotic plaque rupture. The five key opinion leaders from around the globe also suggest ways in which future research could be targeted to address the deficits in our understanding, with the aim of preventing cardiovascular disease, improving patient care, and reducing morbidity and mortality.