A cognitive science analysis of the interaction between psychosocial stress and the neurobiology of affective illness highlights a number of mechanisms relevant to the study of recurrence in major depressive disorder. It builds on observations previously offered by Post (1992) regarding the importance of kindling and sensitization effects in determining activation of neural structures, and proposes a model of knowledge structure activation that follows similar parameters. Vulnerability to depressive relapse/recurrence is determined by the increased risk of particular negative patterns of information processing being activated in depressed states. As is found in studies of kindling and behavioural sensitization, the likelihood of cognitive patterns being activated is dependent on the frequency of past usage, and increased reliance on these patterns of processing makes it easier for their future activation to be achieved on the basis of increasingly minimal cues. This model suggests that the processes related to relapse/recurrence and episode onset may not be isomorphic and, as such, treatments that emphasize relapse prevention strategies should take this distinction into account.