Uncontrollable stress, a major precipitant of depression in humans and in animal paradigms, impairs hippocampal neurogenesis, which is necessary for the behavioral effects of antidepressants in models of depression that require chronic treatment. However, the mechanisms underlying these anti-neurogenic and behavioral effects of stress have not been elucidated. Proinflammatory cytokines are thought to be contributing factors to stress and have been implicated in stress-related mood disorders such as major depression. In particular, IL-1 beta has been proposed to be a key mediator in a variety of behavioral actions of stress. Notably, the administration of a IL-1 receptor antagonist (IL-1Ra) blocks the stress-like effects of IL-1 beta in both cellular and behavioral models. This review highlights the increasing interest in the relationship between IL-1 beta, neurogenesis, stress and depression, and discusses the potential of IL-1Ra or other cytokine antagonists as new candidates for the treatment of depression.