Abstract: Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-α mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.