Challenge of rat parotid slices with substance P or its analogs, at concentrations which cause less than maximal response resulted in the transient release of K+ into the medium. Reuptake of the released K+ into the cell was accompanied by a parallel decrease in the biologically active concentration of the peptide in the medium, indicating that at low concentrations inactivation of the peptide is a mechanism for termination of the substance P response. At concentrations of substance P and its analogs which are higher than needed for a maximal response, a second mechanism for the termination of the response enters into play, resulting in desensitization of the response to substance P. Desensitization was specific for substance P and was not influenced by activation of the cholinergic or alpha-adrenoceptors. Inactivation of the peptide by proteolytic breakdown does not take part in the development of desensitization to substance P.