By influencing the central nervous system, cytokines, which regulate immune function innately and adaptively, may play a key role in mediating depression-like neuro-behavioral changes. However, the similarity between cytokine and stressor-effects in animal models raises a question about the degree to which behavioral and neurochemical outcomes of cytokine challenge represent depressive disorder per se. The present review attempts to illustrate the degree of overlap between cytokines and stressors with respect to their effects on neurochemistry and behavior in animal models. The review also shows how short-term effects of cytokine exposure in typical animals may be discerned from characteristics that might otherwise be described as depression-like. By comparing outcomes of immune challenge in typical rodent strains (e.g., Sprague-Dawley [SD], Wistar) and an accepted animal model of depression (e.g., Fawn Hooded [FH] rodent strain), differences between short-term effects of cytokines and depression-like characteristics in rodents are demonstrated. Additionally, because it is known that preexisting vulnerability to depression may affect outcomes of immune challenge, we further compare immunological, biochemical and behavioral effects of cytokines between SD and FH rodent strains. Interestingly, the acute neurochemical and behavioral effects of the cytokine interleukin 1alpha (IL-1alpha) reveal stressor-like responses during behavioral habituation in both strains, though this appears to a stronger degree in FH animals. Further, the subacute response to IL-1alpha vastly differed between strains, indicating differences in adaptive mechanisms. Thus, stressor-like effects of immune challenge, particularly in FH animals, provide validation for recent "cross-sensitization" models of depression pathogenesis that incorporate immune factors.