Historically, the legislative control of substances with perceived desired psychoactive effects has always triggered a search for non-controlled alternatives, and the appearance of psychoactive substances of predominantly synthetic origin can be traced back to these efforts. In the last decade, so-called new psychoactive substances (NPS) exploded into the consciousness of policy makers, researchers, practitioners, as well as the general public. NPS are typically viewed as substances not listed in the United Nations Single Convention on Narcotic Drugs, 1961, as amended by the 1972 Protocol, or the United Nations Convention on Psychotropic Substances, 1971, that may pose public health or social risks similar to the substances listed therein. Driven by globalization, easy access to NPS, the striking number of substances, their chemical diversity, and the realization that ideas for large-scale production originated from the – sometimes forgotten or otherwise unexplored – scientific literature, along with the growing numbers of life-threatening poisonings and other harms, have moved the NPS phenomenon firmly onto the policy agenda. Consequently, a variety of legislative and other policy responses have been formulated throughout the globe in an effort to protect public health.