Medicines regulation is based on a foundation of science, policy and judgement. It operates within several frameworks (scientific, legal and public health), which are interdependent. While safety, quality and efficacy remain the criteria by which medicines are assessed, the benefit-to-harm balance for any medicine or medical device is of paramount importance. While the regulator was hitherto the gatekeeper who allowed a medicine on to the market, payers now require, in addition, assessment of cost and clinical effectiveness before use. As regulatory frameworks develop, several changes will occur, as follows: (i) formal benefit–harm assessment will become an integral part of submission for marketing authorizations; (ii) there will be greater use of surveillance for adverse reactions to new medicines using methods other than voluntary reporting; (iii) risk management plans will become benefit–risk management plans; (iv) life-saving medicines will be approved earlier; and (v) regulation and health technology assessment will take place simultaneously. Clinical pharmacologists will play important roles in these developments.