The actions of picrotoxinin, bicuculline and penicillin-G were investigated on the GABA-receptor system of lobster muscle by using intracellular recording. The highly potent antagonist, picrotoxinin, produced a lateral shift and depression in the maximum of the GABA dose--conductance curve (designated as mixed antagonism); bicuculline, a weak antagonist, caused only a depression in the maximum with little or no lateral shift, whereas penicillin-G, an even weaker antagonist, produced a greater depression at the top of the dose--response curve. The possible sites of antagonist action were examined, with a critical re-evaluation of a drug-receptor model previously proposed to account for the antagonistic behaviour of picrotoxinin (the mixed antagonistic model); this model was extended to include the actions of bicuculline and penicillin-G. Antagonism was examined (i) towards different GABA receptor agonists; (ii) in various external anion media; (iii) at varying external pH; and (iv) when two different antagonists were combined. The GABA agonists were differentially antagonized by picrotoxinin and bicuculline, but external pH and substituent anions caused only minor perturbations to the inhibition. Combination experiments suggested at least three sites for GABA antagonists binding on crustacean muscle: (i) the GABA recognition site or sites; (ii) the ionic selectivity site in the ionophore; and (iii) a highly lipophilic site which may be part of the GABA receptor or ionophore. The mixed antagonism model accounted for the pH and external anion data but required modification to a cyclic scheme to explain the antagonism of a partial agonist. A model based on two-state receptor theory could only account for the antagonism of GABA if picrotoxinin was assumed not only to perturb L (the R $\rightleftharpoons $ T conformation constant) but also to affect the agonist binding affinity. It is suggested that picrotoxinin and bicuculline may antagonize GABA responses by stabilizing the closed form of the activated channel, whereas penicillin-G may block the channel in the open state.