Staphylococcal enterotoxins are able both to stimulate powerful polyclonal proliferative responses and to induce non-responsiveness of T lymphocytes expressing the appropriate T-cell antigen receptor Vβ gene products. T-cell clones representative of the human response to house dust mite were identified that express either Vβ3 or Vβ6 gene products. The specificity of the latter was confirmed by serology. Pre-treatment of cloned Vβ3+ T cells with the Staphyhcoccus aureus enterotoxins B or C1 rendered them non-responsive to immunogenic challenge with their natural ligand, while retaining responsiveness to exogenous IL-2. Similarly, exposure of the Vβ6+ dust mite reactive T cells to the Staphylococcal enterotoxin of the appropriate specificity, SEE, induced specific anergy. The development of non-responsiveness was associated with changes in the T-cell phenotypes. Downreguiation of the T-cell receptor, Ti-CD3, was paralleled by enhanced expression of both CD2 and the IL-2 receptor, CD25. Differential co-modulation of CD4 and Ti-CD3 suggested that for some T cells CD4 may form part of the specific antigen recognition structure. Toxicity of the Staphylococcal enterotoxins may be removed by chemical modification, thus their ability functionally to inactivate subpopulations of T cells expressing antigen-specific receptors with shared characteristics may be of potential value in the regulation of allergic diseases if the diversity of the T-cell repertoire proves to be limited.