Synthetic cannabinoids (SCBs) are a group of new psychoactive substances (NPS) that strongly affect the endocannabinoid system and promote psychotropic effects similar to those triggered by the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC). Yet, the effects promoted by SCBs are more intense than those elicited by THC and are mainly associated to psychotic symptoms. The abuse potential of these substances has been showed to be higher than cannabis, thus representing a major public health concern. The limited information available on the mechanisms underlying these NPS has stimulated preclinical studies to assess the pharmacology and toxicology associated to acute and chronic use of SCBs. This chapter illustrates the major findings on SCBs coming from pharmacodynamics, pharmacokinetics, toxicological, and behavioral studies. The knowledge related to SCBs’ use is crucial to detect and interpret the clinical cases of intoxications and to develop new targets to treat their induced adverse effects.