Psychoactive substances (PAS) have been known to mankind since times BC when their use was an essential part of the rituals of ancient civilizations. Throughout the following time periods numerous plant species were discovered, and psychotropic effects were achieved by consuming them. In the last century the manufacturing of drugs has moved from nature into the laboratories and thus began the era of synthetic PAS. At the start of the 21st century the spotlight was taken by groups of synthetic drugs that were considered legal, and yet they imitated the effects of classic traditional drugs. These groups of drugs have the common name of new psychoactive substances (NPS), and they consist of aminoindanes, derivatives of phenylethylamine, phencyclidine-like substances, piperazines, synthetic cannabinoids, synthetic cathinones, synthetic opioids, and others. Modern society has been blessed with the development of technology, and yet there are also dangers that it brings. Namely, the Internet has acted as a key jumping-off point for the popularization and global availability of NPS, and especially the appearance of darknet. Consequentially, the manufacturing of these substances has seen a boost, and so every year there appears a new NPS on the market that makes all the legislative attempts to regulate them futile. Like a game of cat and mouse, as soon as one PAS is regulated, there is a new one with comparable effects that replaces the old and takes the market share, thus repeating the cycle. Unfortunately, in this game, the worst consequences are suffered by the people consuming the product. NPS present a substantial challenge to the medical personnel dealing with acutely intoxicated patients. These substances cannot be detected by standard laboratory tests for drugs, so the basic therapy in acute states is strictly symptomatic. Besides that, in comparison with traditional drugs, NPS are generally more potent, and thus, riskier for users. This article describes NPS, clinical pictures and toxidromes (a set of signs and symptoms related to the specific groups of NPS) that are important in the care of patients in acute conditions. Furthermore, cases descriptions are presented based on a literature review. Finally, the need for preventive action to raise knowledge and awareness of this problem in the general population, especially among young people, and the need for interdisciplinary and multidisciplinary cooperation in prevention (physicians, psychiatrists, psychologists, pedagogues, teachers, judiciary, etc.) is pointed out.