Atherothrombosis is responsible for the acute clinical manifestations of atherothrombotic disease, namely coronary artery disease, cerebrovascular disease, and peripheral artery disease. Despite advances in antithrombotic therapies, the residual morbidity and mortality associated with these conditions remain high. The use of more intensive antithrombotic therapies also has to be balanced against their increased risks of bleeding, especially when administered in combination. The situation is further complicated by the fact that indirect comparison of clinical trial data does not lead to definitive conclusions on the best therapeutic approach. Therefore, determining the optimal antithrombotic combinations, which offer the greatest reductions in cardiovascular events without an excess of bleeding, for the broad range of patient populations and clinical scenarios seen today, and encompassing both the acute phase and long-term period remains challenging. I report on the latest data from randomized clinical trials on antithrombotic agents and look to future trials to shed light on this complex therapeutic field.