Fentanyl, a synthetic μ-opioid receptor agonist, is widely used for severe to moderate pain management due to its rapid onset and high potency compared to morphine. However, the abuse of fentanyl and its derivatives has increased globally, particularly in the United States, leading to a significant opioid epidemic. Fentanyl is highly toxic, with a median lethal dose (LD50) of 3.1 mg/kg in rats and 0.03 mg/kg in monkeys. Its abuse can lead to fatal respiratory depression, anaphylactic response, and cardiac issues. The synthesis and derivatization of fentanyl are inexpensive and easily achievable, leading to the emergence of over 1400 fentanyl derivatives. These derivatives, often referred to as "designer fentanyl," are used as less expensive replacements for heroin and pose a significant risk of overdose and death. The review discusses the properties, pharmacology, and overdose cases associated with fentanyl and selected derivatives. It highlights the current opioid epidemic in the US, the Moscow theater hostage crisis, and the potential misuse of fentanyl and its derivatives as chemical weapons. The synthesis, pharmacokinetics, and toxicity of fentanyl and its derivatives, such as acetyl fentanyl, acryl fentanyl, butyryl fentanyl, carfentanil, cyclopentyl fentanyl, cyclopropyl fentanyl, para-fluorobutyl fentanyl, ortho-fluorofentanyl, and furanyl fentanyl, are detailed. These derivatives exhibit varying affinities to opioid receptors and have been linked to numerous overdose deaths in the US and Europe. The review also emphasizes the importance of treatment options, such as naloxone, for managing fentanyl overdoses.Fentanyl, a synthetic μ-opioid receptor agonist, is widely used for severe to moderate pain management due to its rapid onset and high potency compared to morphine. However, the abuse of fentanyl and its derivatives has increased globally, particularly in the United States, leading to a significant opioid epidemic. Fentanyl is highly toxic, with a median lethal dose (LD50) of 3.1 mg/kg in rats and 0.03 mg/kg in monkeys. Its abuse can lead to fatal respiratory depression, anaphylactic response, and cardiac issues. The synthesis and derivatization of fentanyl are inexpensive and easily achievable, leading to the emergence of over 1400 fentanyl derivatives. These derivatives, often referred to as "designer fentanyl," are used as less expensive replacements for heroin and pose a significant risk of overdose and death. The review discusses the properties, pharmacology, and overdose cases associated with fentanyl and selected derivatives. It highlights the current opioid epidemic in the US, the Moscow theater hostage crisis, and the potential misuse of fentanyl and its derivatives as chemical weapons. The synthesis, pharmacokinetics, and toxicity of fentanyl and its derivatives, such as acetyl fentanyl, acryl fentanyl, butyryl fentanyl, carfentanil, cyclopentyl fentanyl, cyclopropyl fentanyl, para-fluorobutyl fentanyl, ortho-fluorofentanyl, and furanyl fentanyl, are detailed. These derivatives exhibit varying affinities to opioid receptors and have been linked to numerous overdose deaths in the US and Europe. The review also emphasizes the importance of treatment options, such as naloxone, for managing fentanyl overdoses.