Background: Novel psychoactive substances (NPS) are compounds of natural and synthetic origin, similar to traditional drugs of abuse. NPS are involved in a contemporary trend whose origin lies in a thinner balance between legitimate therapeutic drug research and legislative control. The contemporary NPS trend resulted from the replacement of MDMA by synthetic cathinones in ‘ecstasy’ during the 2000s. The most common NPS are synthetic cannabinoids and synthetic cathinones. Interestingly, during the last 50 years, these two classes of NPS have been the object of scientific research for a set of health conditions. Methods: Searches were conducted in the online database PubMed using boolean equations. Results: Synthetic cannabinoids displayed protective and therapeutic effects for inflammatory, neurodegenerative and oncologic pathologies, activating the immune system and reducing inflammation. Synthetic cathinones act similarly to amphetamine-type stimulants and can be used for depression and chronic fatigue. Conclusions: Despite the scientific advances in this field of research, pharmacological application of NPS is being jeopardized by fatalities associated with their recreational use. This review addresses the scientific achievements of these two classes of NPS and the toxicological data, ending with a reflection on Illicit and NPS control frames.