Hydrofluoric acid (HF) induces severe skin necrosis through corrosive damage and tissue toxicity. As it is only partially dissociated (pKa 3.2), the small HF molecule penetrates deeply into tissues. When absorbed into the circulatory system, HF can dissociate into H+ and F- ions (the latter binds calcium and magnesium and releases potassium from erythrocytes), which together with resultant severe metabolic acidosis may result in cardiovascular system toxicity with dysrhythmias and death. A review of human occupational accidental HF exposures and recent experimental data from human skin explant ex-vivo studies was performed. Lesions due to 70% HF appeared within the first minute on human skin explants and full skin penetration was observed within 5 minutes. Human accidental occupational exposure has occurred with 70% HF, 40% HF, and 6-15% HF/Nitric acid ("pickling acid"), and while water washing has traditionally been used, Hexafluorine® has been found to be efficacious in these circumstances. Even with delayed use of this specific decontamination solution in 70% HF burns, the results compared with historical cases has been promising for preventing serious burns and systemic toxicity or mitigating them. A more recent experimental technique, using human skin explants obtained from abdominoplasty patients preserved ex vivo offers a method of evaluating the effects of corrosive substances and their mitigation with active decontamination solutions versus water irrigation in intact human skin. Hexafluorine® used in this ex vivo model was more efficacious than tap water irrigation followed by calcium gluconate ointment. Decontamination of skin hydrofluoric acid exposure should be ideally started within the first minute. Traditionally, the initial decontamination has been with tap water in an industrial safety shower following recommendations such as those found in the ANSI/ISEA Z358.1-2009 Standard or similar European Norms, which has mitigated the effects of HF skin exposure in certain cases. However, recent clinical and ex vivo human skin explant data suggest that, when available, Hexafluorine® may be a more efficacious alternative decontamination solution. In every case, calcium gluconate appeared.