Advances in chemistry, technology, and globalization have contributed to the rapid development and diffusion of NPS (new psychoactive substances), creating perhaps the most serious challenge to the century-old international drug control system and to national systems. Very little is known about the effects of these substances which fall outside of national and international controls. The predominant response to the flood of NPS has been the development of more expeditious methods of prohibiting a new chemical entity. This article explores alternative mechanisms that have been considered: foodstuffs, alcohol and tobacco and medicines. None seems promising in terms of avoiding the problems of prohibition without permitting unsafe substances on the market. The article then considers whether there is a bias in the existing system toward excessive prohibition. In public discussion, no attention is given to the pleasures that users obtain from any NPS, to the possibility of substitution for a more dangerous legal or illegal drug or to the consequences of illegal markets for prohibited NPS. On the other hand, it may well be impossible to obtain meaningful assessments on any of these matters at the time when decisions are made. These complexities have led a number of countries, most recently Australia and the UK, to impose total bans, the effects of which are impossible to predict.