Digoxin is eliminated by the kidneys through P-gp, a drug efflux pump. Young children require higher doses of digoxin than adults, due to a higher clearance rate of the drug. We hypothesized that there is an increase in P-gp expression in young children, leading to higher tubular secretion of the glycoside. We tested this hypothesis in mice. Semi-quantitative RT-PCR was conducted to analyse mdr1a and mdr1b ontogeny in the kidney at: birth, 7, 14, 21, 28 and 45-day old FVB mice. Clearance studies were conducted in parallel. At 21 days, which is the period of weaning in mice, we observed the highest mdr1b expression, and the highest clearance rate of digoxin. The renal ontogeny of P-gp is likely an important mechanism of age-dependant digoxin clearance in young children. Our study documents an ontogeny of renal P-gp, explaining why younger children need substantially higher doses of this drug.