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Cnidaria include the most venomous animals of the world. Among Cnidaria, Scyphozoa (true jellyfish) are ubiquitous, abundant, and often come into accidental contact with humans and, therefore, represent a threat for public health and safety. The venom of Scyphozoa is a complex mixture of bioactive substances—including thermolabile enzymes such as phospholipases, metalloproteinases, and, possibly, pore-forming proteins—and is only partially characterized. Scyphozoan stings may lead to local and systemic reactions via toxic and immunological mechanisms; some of these reactions may represent a medical emergency. However, the adoption of safe and efficacious first aid measures for jellyfish stings is hampered by the diffusion of folk remedies, anecdotal reports, and lack of consensus in the scientific literature. Species-specific differences may hinder the identification of treatments that work for all stings. However, rinsing the sting site with vinegar (5% acetic acid) and the application of heat (hot pack/immersion in hot water) or lidocaine appear to be substantiated by evidence. Controlled clinical trials or reliable models of envenomation are warranted to confirm the efficacy and safety of these approaches and identify possible species-specific exceptions. Knowledge of the precise composition of Scyphozoa venom may open the way to molecule-oriented therapies in the future.