The theoretical framework, by which we understand the function of NMDA receptors, is derived, in large part, from work conducted on the hippocampal slice preparation, where NMDA receptors are crucial for a form of synaptic plasticity known as long-term potentiation (LTP). Establishing their role in plasticity mechanisms in the neocortex is proving to be far more difficult than originally envisaged, in part due to the fact that the operation of NMDA receptors is different in the intact animal than in vitro. For example, NMDA receptors are activated at low levels of sensory input in intact animals but only by high levels of input in slice preparations. Recent results suggest that a re-evaluation of the role of NMDA receptors in neocortical plasticity is required. Here we discuss some of the issues and introduce four criteria by which any factor supposedly involved in plasticity can be judged. NMDA receptors fulfill more of these criteria than any of the other factors so far investigated in the visual cortex, but maybe this is because they have been studied more intensively.