Avermectins and milbemycins are an important family of anthelmintics, insecticides and acaricides. Their mode of action is as positive allosteric modulators of ligand-gated chloride channels, and at higher concentrations, they gate some channels directly. Though it has long been known that the avermectins do not compete for the ligand binding site, the actual site at which they interact with their receptors has been unclear. Recent data demonstrate the importance to drug binding of amino acid residues predicted to line a water-filled pocket in the channel domain. This pocket acts as the binding site for anaesthetics and other modulators of mammalian GABA(A) and glycine receptors, suggesting similarities in the mode of action between these drugs and the avermectins/milbemycins.