These studies investigated the effect of met-enkephalin, glycyl-glutamine, and naltrexone on NK cell activity in vivo and in vitro. It was found that both met-enkephalin (which shares the amino-terminal end of beta-endorphin) and glycyl-glutamine (which reflects the carboxyl-terminal end of beta-endorphin) can enhance the NK cell activity of mice prestimulated with a low dose (1 microgram/mouse) of poly I:C. Naltrexone had no effect. In vivo prestimulation of the mice with 1 microgram poly I:C was necessary as mice which were not pretreated with poly I:C did not show enhanced NK cell activity when treated with either met-enkephalin or glycyl-glutamine. In vitro studies however indicate that the drugs when cultured together with the NK cells from mice preactivated with poly I:C did not have a direct stimulatory effect on the NK cells. These studies imply that while beta-endorphin released from the pituitary could be involved in enhancement of activated NK cells in vivo other indirect peripheral pathways might be involved. The results suggest beta-endorphin probably reacts with other accessory type cells which in turn release the mediators which are required for the stimulation of NK cells in vivo.