In ligand-gated ion channels the perturbation introduced by the binding of the neurotransmitter to the extracellular domain results in the opening of the channel gate. The details of the dynamics of this process are hard to establish and remain the subject of much investigation. Our main approach is to analyse single-channel data by global fitting of activation mechanisms. Applying this technique to glycine-gated channels allowed us to identify and characterize a functional state that, in the pathway of activation, is an intermediate between the resting closed state and the open state. At this intermediate state, which we termed the ‘flipped’ state, the channel is still closed, but has undergone a conformational change that has increased its affinity for the agonist to a level intermediate between that of the resting state and that of the open state. This property, taken together with what we know about the structure of the resting and open states, suggests that the ‘flipped’ state may represent the closure of the agonist binding domain onto the agonist molecule. The greater detail included in the ‘flip’ mechanism has allowed us to re-examine the fundamental question of agonist efficacy. In both the ACh muscle nicotinic and the glycine channels, we found that low efficacy reflects mostly the inability by the agonist to bring about the pre-opening conformational change. The actual open-shut reaction is much the same for full and partial agonists.