Over the last decade, the “traditional” drug scene has been supplemented – but not replaced – by the emergence of a range of novel psychoactive substances (NPS), which are either newly created or existing drugs, including medications, now being used in novel ways. By the end of 2015, in excess of 700 NPS had been reported by a large number of countries in the world. Most recent data show however that synthetic cathinones; synthetic cannabinoids; and psychedelics/phenethylamines; account for the largest number of NPS. Given the vast range of medical and psychopathological issues associated with the molecules here described, it is crucial for health professionals to be aware of the effects and toxicity of NPS. The “Drugs 2.0.” revolution facilitated the birth and growth of an “Online Drug Culture” which finds its main expression in chats/fora/blogs as well as the diffusion of online drug marketplaces (both in the surface and deep web). The web has progressively modified the drug market from a “street” into a “virtual” one, so by increasing the availability of new drugs/NPS/“legal highs” (“legal alternatives” to the traditional illegal drugs). The rapid pace of change in the NPS online market constitutes a major challenge to the provision of current and reliable scientific knowledge on these substances. The present lecture aims at providing an overview of the NPS phenomenon, also giving an overview of the main clinical and pharmacological issues relating to these most popular NPS categories.