The abuse of drugs is a widespread and growing issue, both in United States and Europe, as a number of synthetic drugs have raised popularity over the past years for recreational use. Moreover, the nature of addiction is often debated as either a lifestyle choice that may underline a physiological vulnerability, and achievements in neuroscience identified addiction as a chronic brain disease with remarkable epigenetic, neurodevelopmental and sociocultural components. Consciousness and treatment of new drugs of abuse give challenges for health care practitioners primarily due to a lack of quantitative reports. As law enforcements struggle to ban these often referred as “legal highs”, new compounds are produced. Also, a major problem in tracking these drugs is that they are easily available through head shops, the web and other sources, therefore giving rise to a high risk of suspected intoxication. The aim of this article is to highlight the pharmaco-toxicological features of some common drugs of abuse currently more “fashionable” such as central nervous system stimulants as synthetic cannabinoids, synthetic cathinones, gabapentin, acetyl fentanyl, phenethylamine called NBOMe, hallucinogenic mushrooms, piperazines, tryptamines, salvia, methoxetamine, kratom and performance-enhancing drugs. The tremendous heterogeneity of these drugs results in variable pharmacokinetic and pharmacodynamic effects, thus suspected intoxication is a priority diagnosis in order to ensure safety of patients and needs to be handled with the guide of the patient’s symptoms through specific and detailed urine and blood analysis.