Repeated injections of rats with compound 48/80, a histamine liberator, results in a marked increase in histidine decarboxylase activity of the skin. The increase is roughly proportional to the duration of treatment. This eliminates activation of pre-existing histidine decarboxylase as a probable mechanism. The increase can be demonstrated in intact rats; therefore, rat skin histidine decarboxylase is an adaptive enzyme. It seems probable that 48/80 treatment leads to the production of new, resistant mast cells which are particularly active in forming histamine. This speculation is compatible with reports from other laboratories of histological studies on rats given 48/80. Implications of this finding are discussed.