Work in our laboratory has focused on the mechanisms by which cytokines can influence the brain and behavior in humans and non-human primates. Using administration of interferon (IFN)-alpha as a tool to unravel these mechanisms, we have expanded upon findings from the basic science literature implicating cytokine-induced changes in monoamine metabolism as a primary pathway to depression. More specifically, a role for serotonin metabolism has been supported by the clinical efficacy of serotonin reuptake inhibitors in blocking the development of IFN-alpha-induced depression, and the capacity of IFN-alpha to activate metabolic enzymes (indolamine 2,3 dioxygenase) and cytokine signaling pathways (p38 mitogen activated protein kinase) that can influence the synthesis and reuptake of serotonin. Our data also support a role for dopamine depletion as reflected by IFN-alpha-induced changes in behavior (psychomotor slowing and fatigue) and regional brain activity, which implicate the involvement of the basal ganglia, as well as the association of IFN-alpha-induced depressive-like behavior in rhesus monkeys with decreased cerebrospinal fluid concentrations of the dopamine metabolite, homovanillic acid. Neuroimaging data in IFN-alpha-treated patients also suggest that activation of neural circuits (dorsal anterior cingulate cortex) associated with anxiety and alarm may contribute to cytokine-induced behavioral changes. Taken together, these effects of cytokines on the brain and behavior appear to subserve competing evolutionary survival priorities that promote reduced activity to allow healing, and hypervigilance to protect against future attack. Depending on the relative balance between these behavioral accoutrements of an activated innate immune response, clinical presentations may be distinct and warrant individualized therapeutic approaches.