The regulation of medicine requires evidence of the efficacy and safety of medicines, and methods are well-developed to deal with the latter and to a lesser extent the former. However, until recently, assessment of risk- benefit especially in relation to alternatives has been entirely informal. There is now growing interest in the possibilities of more formal approaches to risk-benefit decision-making. In this talk, we review the basis of drug regulation, the statistical basis for decision-making under uncertainty, current initiatives in the area, and discuss possible approaches that could enhance the quality of regulatory decision-making, drawing on experience of the IMI PROTECT project.