Novel psychoactive substances are newly used designer drugs ("internet drugs", "research chemicals", "legal highs") potentially posing similar health risks to classic illicit substances. Chemically, many novel psychoactive substances can be classified as phenethylamines, amphetamines, synthetic cathinones, piperazines, pipradrols/piperidines, aminoindanes benzofurans, and tryptamines. Pharmacologically, these substances interact with various monoaminergic targets. Typically, stimulants inhibit the transport of dopamine and noradrenaline (pipradrols, pyrovalerone cathinones) or induce the release of these monoamines (amphetamines and methamphetamine-like cathinones), entactogens predominantly enhance serotonin release (phenylpiperazines, aminoindanes, para-substituted amphetamines, and MDMA-like cathinones) similar to MDMA (ecstasy), and hallucinogens (tryptamines, hallucinogenic phenethylamines) are direct agonists at serotonergic 5-HT2A receptors. Synthetic cannabinoids are another group of novel substances which all act as agonists at the cannabinoid CB1 receptor similar to THC but are chemically diverse. In particular, the relative serotonergic vs dopaminergic activity (determined by the dopamine/serotonin transporter inhibition ratio in vitro) can be helpful to predict the desired psychotropic but also the toxic effects of novel substances as well as their potential for addiction. Although the use of novel psychoactive substances mostly produces minor or moderate poisonings, serious complications occur. Serotonergic drugs (entactogens and hallucinogens) are associated with acute serotonin syndrome, hyperthermia, seizures, and hyponatremia. Dopaminergic drugs are highly addictive and acute toxicity includes prolonged stimulation, insomnia, agitation, and psychosis. Agitation, anxiety, paranoia, hypertension, and rarely myocardial infarction and renal failure are seen with synthetic cannabinoids. Treatment is supportive.