In many patients, depression takes a recurrent or chronic course, in which maintaining mechanisms becomes increasingly engrained, and repeated stress translates into significant changes in biological functioning. The introduction of mindfulness training has brought a paradigmatically new approach to the treatment of persistent courses of depression that promises to counter such mechanisms and thus offers potential to eventually reverse maladaptive plasticity. However, research on biological mechanisms of mindfulness training in this domain is still widely lacking. In order to encourage such research, we outline psychobiological mechanisms underlying persistent depression, discuss why mindfulness training may be particularly suited to address these mechanisms, and review current evidence supporting the potential for reversibility. We conclude by emphasizing the need for studies investigating sustained training in mindfulness in order to elucidate the timescales of cascading effects and in how far these effects translate into changes in otherwise persistent trajectories.