We propose a framework to understand increases in vulnerability for depression after recurrent episodes that links attention processes and schema activation to negative mood states, by integrating cognitive and neurobiological findings. Depression is characterized by a mood-congruent attentional bias at later stages of information processing. The basic idea of our framework is that decreased activity in prefrontal areas, mediated by the serotonin metabolism which the HPA axis controls, is associated with an impaired attenuation of subcortical regions, resulting in prolonged activation of the amygdala in response to stressors in the environment. Reduced prefrontal control in interaction with depressogenic schemas leads to impaired ability to exert attentional inhibitory control over negative elaborative processes such as rumination, leading in turn to sustained negative affect. These elaborative processes are triggered by the activation of negative schemas after confrontation with stressors. In our framework, attentional impairments are postulated as a crucial process in explaining the increasing vulnerability after depressive episodes, linking cognitive and biological vulnerability factors. We review the empirical data on the biological factors associated with the attentional impairments and detail how they are associated with rumination and mood regulation. The aim of our framework is to stimulate translational research.