The natural history of non-alcoholic fatty liver disease (NAFLD) is still not fully elucidated. Patients with NAFLD have a low risk of liver complications, unless substantial liver fibrosis has developed. On the other hand, NAFLD has been linked with excess metabolic and cardiovascular complications. Therapies targeting common pathways may benefit both NAFLD and underlying cardiometabolic risk. Therefore, there is a rationale for considering cardiovascular endpoints in the context of NAFLD trials and, vice-versa, to consider the concomitant presence of NAFLD in drug development for cardiometabolic disorders. This manuscript provides a framework for consideration for future trials examining the inter-relationship between cardiovascular disease and NAFLD.