The authors have used computer simulation to examine the time course of the plasma concentration, estimated effect site concentration, and the intensity of the central nervous system (CNS) effect of fentanyl and alfentanil. The simulations were performed over a range of clinically equivalent doses. Simulations of the changes in the processed electroencephalogram (EEG) was used as a reflection of drug induced CNS effect. The simulations reveal that the rate of equilibration between effect site and plasma concentrations can explain differences in the clinical time course of drug effect between these opioids. The onset of fentanyl EEG drug effect is delayed relative to alfentanil and the duration of action is longer. Pharmacokinetic differences do not explain the disparity seen in the time courses of EEG drug effect. Alfentanil and fentanyl have similar plasma disposition curves during the first 90 min. The concentrations at the effect site are, however, quite different. The simulations illustrate how fentanyl's slow blood:brain equilibration can dampen the rate of rise and fall of effect site concentrations. As a mechanism for terminating effect, redistribution of opioid from effect site to other body regions is less relevant for fentanyl compared with that for alfentanil. The evanescent clinical effects of alfentanil can be explained by the rapid blood:brain equilibration. Computer simulation is a useful tool for revealing relevant determinants of the complex relationship between dose and the time course of effect.