The influence of age on tissue distribution of digoxin in mice and guinea pigs and uptake by mouse heart slices was investigated. 4 h after a single dose of 3H-digoxin, tissue:plasma ratios were significantly greater in very young animals and declined with increasing age. A similar relationship was apparent for packed red blood cell:plasma concentration ratios in mice. Uptake of 3H-digoxin by heart tissue slices was also higher for 21-day-old mice than 200-day-old mice. These data seem to correlate with the larger volume of distribution of digoxin observed in the young. Tissue digoxin relative to plasma concentration seems higher in the young, although they appear less sensitive to the effects of cardiac glycosides.