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On the premise that an antibody combining site is a mirror image of its antigen epitope, it is expected that an anti-idiotypic antibody (i.e., an antibody specific for the combining site of the first antibody) will be homologous to the epitope. Anti-idiotypic antibodies raised against hormones or drugs would, therefore, be anticipated to interact with their respective receptors. According to this schema, anti-idiotypic antibodies could either be antagonists or agonists. Most of the anti-idiotypic antibodies raised against hormones and neurotransmitters to date have proved, however, to be agonists. We have raised antithyrotropin (anti-TSH) anti-idiotypic antibodies and found these to interact with the high affinity binding site for TSH on thyroid plasma membranes and to induce cGMP-dependent adenylate cyclase activation and iodide transport into dispersed thyroid cells, as well as to promote their organization into follicular structures. The anti-TSH anti-idiotypic antibody interacted with a holoreceptor band of relative mass (Mr) ~ 200 000, resolved on sodium dodecyl sulfate – polyacrylamide gel electrophoresis from thyroid membranes and transferred to nitrocellulose paper. In another set of experiments we raised anti-idiotypic antibodies against monoclonal antibodies specific, respectively, for the α and β subunits of TSH. Neither the α nor β monoclonal antibody specific anti-idiotypic antibodies interacted with the TSH holoreceptor. The combinations of the two anti-idiotypic antibodies, however, did so and increased basal cyclase activity significantly compared with normal immunoglobulin G. As a result of the second set of experiments, we propose that the interaction of TSH with its receptor involves two signals delivered by the two subunits rather than a single signal requiring their combination. Anti-idiotypic antibodies raised against highly purified hormones can be obtained in large amounts. They facilitate simple isolation of hormone receptors and are useful as probes for hormone–receptor interactions.