An aggressive pharmaco-interventional approach has been shown to improve long-term outcome among high-risk patients with acute coronary syndromes without ST-segment elevation (NSTEACS). However, these patients continue to represent a minority among those enrolled in clinical trials, thus precluding the possibility to further improve therapeutic efficacy. Target populations that are not adequately addressed by the majority of therapeutic trials are mainly the elderly and those with reduced renal function, who all show unfavorable outcome after an episode of NSTEACS. In order to allow comparison among different studies, a prerequisite for the planning of meaningful trials should be a uniform definition of the study end points besides mortality, particularly with reference to recurrent myocardial infarction, and rehospitalization owing to cardiovascular instability or severe bleeding. In addition to trial design issues, improvements in the regulatory rules for drug development and in hospital networking conceal significant opportunities to improve treatment of NSTEACS.