Evidence implicates chronic psychological stress as a precipitating factor in the development of a depressive disorder, as well as decreases in cellular plasticity within the brain. Concordantly, pro-inflammatory cytokines elicit changes in both neurochemistry and behavior reminiscent of psychological stressors, and thus may have a detrimental impact upon neuroplasticity. As previous findings have shown that cytokines and stressors may induce such changes through synergistic interactions, the present study consisted of a series of 3 experiments regarding the role of chronic unpredictable stress (CUS) in tandem with either intraperitoneal injection (1.0 :g) or gene knock-out of cytokines Interleukin-6 (IL-6) or Interferon-gamma (IFN-(). Results indicate that mice exposed to CUS in the absence of cytokine injection demonstrate increased neuron birth within the dentate gyrus of the hippocampus as measured by immunohistochemical doublecortin (DCX) staining, and that CUS in tandem with IFN-( gene knock-out has a similar effect. Results also indicate that CUS exposure produces increases of dentate brain-derived neurotrophic factor (BDNF) expression, which may contribute in part to observed alterations in dentate neurogenesis. Concordantly, treatment with IFN-y decreases immunological and hypothalamic-pituitary-adrenocortical (HPA) axis activity, whereas treatment with IFN-y increases cdl lb+ staining, as well as IL-6 administered in the absence of CUS. Probable mechanisms underlying the present results are addressed in the discussion, along with suggestions for profitable future research. Finally, our results are discussed within the larger context of how altered hippocampal neurogenesis might serve as a causal factor in a depressive episode.