Chemical warfare agents (CWAs) are extremely potent toxic compounds. Even small droplets of CWA, which cannot be seen or felt, may contaminate unprotected soldiers, civilians, or first responders directly on the skin or through seams/tears in protective gear. Vesicants (mustard, HD) induce blisters, ulceration, and necrosis hours after exposure, must penetrate skin but alkylation of biological compounds occurs within minutes. Organophosphate (OP) CWAs, inhibitors of cholinesterases, can lead to a cholinergic crisis, respiratory failure, and ultimately death, and in this case symptoms can be observed within minutes. Thus, the first criterion for personal decontamination is availability of decontamination materials within minutes. Equally important is the ability to neutralize the CWA, extraction of any percutaneous agent, ease of use by self or buddy, and safety. While the skin offers an excellent barrier to many compounds, it is a large and readily accessible surface area for absorption of HD and OPs, which exhibit both lipid and aqueous solubility. Reduction in long-term care after CWA exposure can best be accomplished by rapid on-site detection, decontamination, and detoxification. The M291 dry charcoal resin pad’s effectiveness depends essentially on physical removal and offers minimal detoxification of CWAs, while water (or water with soap or water with hypochlorite) was shown to increase systemic penetration of pesticides. To improve upon current regimens for cutaneous chemical warfare agent exposure, we have been developing polyurethane foam (PUF) sponges that contain additives to extract CWAs from and decontaminate the skin and subsequently detoxify the CWAs to prevent any further contamination, as well as assay techniques to quantify the decontamination process and the detoxification kinetics. The protection afforded by the PUF sponges to CWA exposure was correlated with a) removal of CWAs from shaved guinea pig skin and b) neutralization of the agents. Decontamination and detoxification were quantified using specific and sensitive enzymatic assays for HD and OPs. An in vitro skin permeation assay, a liquid penetration cell test using abdominal porcine skin, was also used to determine the ability of various formulations of PUF additives to penetrate skin with CWA reactants or to remove simulants from the tissue. Compared to the M291 field kit, the PUF sponges provided markedly increased protection for guinea pigs exposed to the neat OPs soman (GD) and VX, as well as reducing methylene blue HOME uptake, edema, and histopathology scoring index in HD exposed animals. Decontamination of these animals occurred in less than 5 min. Thus, PUF sponges provide a tremendous improvement of skin decontamination treatment then presently fielded kit(s).