Experiments were conducted using non-enzymatic chemical agents (with emphasis on certain mercaptans), alone, in conjunction with enzymatic agents and/or other nonenzymatic chemicals for debridement of burns. Both in vitro (rats, pigs, humans) and in vivo (rats, pigs) tests were carried out. N-acetylcysteine, penicillamine and cysteine ethyl ester in low to moderate concentrations accelerate the debriding action of bromelain (an enzymatic preparation from pineapple stems) and in higher concentrations, N-acetylcysteine and penicillamine (cysteine ethyl ester was not tested) cause ready separation of the burn eschar from the underlying tissue before solubilization of the eschar is complete (rat) or has occurred (pig). Debridement of 3° burns of rats is complete within 4–6 hours; the take of immediately applied syngeneic skin grafts is complete and permanent. This is the first time rapid debridement of 3° burns permitting immediate successful skin grafting has been accomplished with known defined chemicals. In pigs there is softening of the 3° burn eschar by N-acetylcysteine but little, if any, dissolution of the eschar. However, mechanical separation of the eschar from the underlying tissue is accomplished readily with a wooden throat stick with no bleeding. There is a change in color of the superficial layer of the underlying subcutaneous tissue from yellow-light brown to dark brown-black. The debrided areas begin to granulate promptly. The healing of deep dermal burns of pigs is hastened by the application of N-acetylcysteine for a day (beginning 24 hours after burning) while the healing of moderately deep dermal burns is not modified. Unburned skin is not damaged. There is no apparent systemic toxicity associated with the use of N-acetylcysteine for debridement of 10–15% b.s.a. 3° burns of rats or 15–20% b.s.a. 3° burns of pigs. Major emphasis has been on N-acetylcysteine because of the potential adverse secondary effect of penicillamine and cysteine ethyl ester; N-acetylcysteine is readily metabolized. The use of a keratolytic agent prior to the application of N-acetylcysteine hastens the latter's action. Sulfamylon and sulfadiazine can be used with N-acetylcysteine without interfering with its debriding action. The effects of the mercaptans are likely due largely to their ability to depolymerize connective tissue proteoglycans and proteins, especially at the interface between living and dead tissue.