An increasing number of novel psychoactive drugs are currently available and sold as 'legal highs' or 'research chemicals'. These New Psychoactive Substances (NPS) constitute a broad range of hundreds of natural and synthetic drugs, including synthetic cannabinoids, synthetic cathinones, synthetic opioids and other classes, which use has resulted in a significantly growing number of intoxication and mortality, as reported by emergency and poison centres from all over the world. Definition of “NPS” includes any substance that has recently become available and has been designed purposely to replace illegal drugs, although not necessarily of new synthesis. Use of NPS is dramatically increased in the last decade and represents a serious risk for the public health. Their ever-evolving chemical structure, the possibility to distribute in real time through the Internet and social networks information about their use and effects have dramatically challenged public health and drug policies internationally. NPS recently attracted great attention, but most are still unregulated and proposed online as legal alternatives to traditional illicit drugs. Unfortunately, this area is still poorly investigated and very limited information are available so far on their nature and potential risks. The phenomenon of NPS requires multi-national and multi-disciplinary collaborations to improve our knowledge on this changing drug market, to share information and define good practices at a global level. Political and educational efforts are indispensable to regulate this mutable scenario and to inform the public about health consequences of NPS use. Clinicians and emergency staff should be aware that NPS may cause severe health consequences and unexpected adverse effects, and be informed on how to recognized and treat specific intoxication cases. Considering the widespread use of NPS and paucity of information about their toxicology and pharmacology, this Research Topic will be useful to understand the new trends in the scenario of drug use, abuse and addiction to inform professionals and general public about the health problems caused by NPS and to help drug-control policies to adopt suitable control measures.