The disposition of epipodophyllotoxins is understood in considerable detail compared to other anti-cancer agents. Recent insights into the pharmacokinetic-pharmacodynamic relationship between etoposide and teniposide systemic exposure and both toxicity and outcome offer a basis for more rational approaches to drug dosage, with the emphasis on systemic exposure achieved, rather than the amount of drug administered per body surface area. Recent studies indicate that chronic--for example 21 days--administration of low dose etoposide may be a more effective dosage schedule for some malignancies. Until the longer term toxicities have been assessed, enthusiasm for this new dosage schedule must be tempered by the potential for greater risk of second malignancies, which has been associated with the frequent--weekly or twice weekly--administration of larger intravenous doses. Measurement of active intracellular drug (and metabolite) concentrations have identified correlations for toxicity and clinical efficacy for such drugs as methotrexate, 6-mercaptopurine, cytarabine and platinum complexes (Plunkett et al, 1985; Reed et al, 1987; Lennard and Lilleyman, 1989; Whitehead et al, 1990). Similar approaches are feasible for the epipodophyllotoxins and may provide an additional strategy for further improvement in the use of these active compounds.