This article presents some recent work from our laboratory indicating that multiple physiological systems play a role in conditioned immunomodulation. The first study shows that naltrexone, but not N-methylnaltrexone, blocks the suppressive effects of an aversive conditioned stimulus on Con-A-induced proliferation and natural killer cell activity of splenic lymphocytes. This finding indicates that central opioid activity is involved in the conditioned effects. The second study shows that the β-adrenergic antagonists atenolol and ICl-118,551 block the suppressive effects of an aversive conditioned stimulus on Con-A-induced proliferation, but have no effect on natural killer cell activity. This result indicates the involvement of the adrenergic system in a subset of the conditioned effects. Collectively, these experiments provide evidence that both the opioid system and the sympathetic nervous system are involved in conditioned immunomodulatory changes elicited by an aversive conditioned stimulus.