In vitro uptake of 11 lipophilic model compounds into rat epididymal adipose tissue slices, adipocytes, triglycerides, and lecithin was studied. Relative uptake at equilibrium into adipose tissue slices increased from 6 to 87% in the following sequence: phenazone, morphine less than pentobarbital less than glutethimide, phenylbutazone less than thiopental, methadone less than chlorpromazine, imipramine. In the presence of albumin a similar sequence was obtained at lower uptake levels, with DDE and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) on top with 95% uptake. However, the time to reach equilibrium was unproportionately greater for DDE and 6-CB (16-40 hr) than for other compounds (1-4 hr). A linear positive correlation was found between relative uptake and partition coefficient (octanol/water). Relative uptake was independent of drug concentration. There were no significant differences between uptake values measured with adipose tissue slices, adipocytes, triolein, and a saturated short-chain triglyceride. In contrast, uptake into lecithin was not correlated with the octanol partition coefficient. Thiopental, imipramine, and 6-CB were taken up into lean tissue slices (liver, lung, skin) in excess of their lipid content, suggesting additional binding sites. Release from preloaded adipose tissue slices followed first order kinetics, was accelerated by albumin, and was much slower for 6-CB and DDE than for thiopental and imipramine. The results indicate that uptake of lipophilic xenobiotics in vitro is a partition process between the aqueous medium and the triglyceride of the adipose tissue preparation. In contrast, the extent of adipose tissue storage of drugs in vivo has recently been shown not to correlate with octanol partition coefficients.