Cardiovascular disease (CVD) remains a leading cause of death and disability worldwide. Acute myocardial infarction (AMI) causes irreversible myocardial damage, heart failure, life-threatening arrythmias and sudden cardiac death (SCD), and is a main driver of CVD mortality and morbidity. To control the forecasted increase in CVD burden for both the individual and society, improved strategies for the prevention of AMI and SCD are required. Current prevention of AMI and SCD is directed towards risk-modifying interventions, guided by risk assessment using clinical risk prediction scores (CRPSs) and the coronary artery calcium score (CACS). Early detection of more advanced coronary artery disease (CAD), beyond risk assessment by CRPSs or CACS, is a promising strategy to allow personalized treatment for the improved prevention of AMI and SCD in the general population. We review evidence for further testing, beyond CRPSs and CACS, and therapies focusing on promising targets, including subclinical obstructive CAD, high-risk plaques, and silent myocardial ischemia. We also evaluate the potential of multi-modality imaging to enhance the conduction of adequately powered trials to provide high-quality evidence on the impact of add-on tests and therapies in the prevention of AMI and SCD in asymptomatic individuals. To conclude, we discuss the occurrence of AMI and SCD in individuals currently estimated to be at "low-risk" by the current strategy based on CRPSs, and methods to improve prevention of AMI and SCD in this "low-risk" population.