Fentanyl is a full synthetic opioid acting as a strong µ-opioids receptor agonist. As other opioids, it exerts effects on central nervous systems like euphoria, sedation, anesthesia and respiratory depression at high dosage. It is the parent compound of the high potent opioids class, characterized by a potency up to 10,000 fold higher than mor- phine, currently prescribed as anesthetic and pain killers. Anyway, the diversion of fentanyl analogues has been reported since their appear- ance on the market, rising until alarming rate. Every year, new synthetic alternatives to the controlled fentanyl are proposed on the black market causing an increasing number of fatalities all over the World. Due to the high potency of this class of substances, it may be difficult to ana- lytically detect the molecules in biological matrices and find the actual cause of the deaths. Moreover, an additional analytical challenge is represented by the emergence of newly synthesized derivatives. In this concern, the harmonization of international guidelines, the adoption of common legal responses and the enforcement of international collaboration is desirable to face this alarming public health threat.