The pharmacokinetics of most anticancer drugs are highly variable in children, and are commonly different when children are compared to adults. Several recent studies have demonstrated that variability in systemic exposure due to interpatient pharmacokinetic variability, may be related to the probability of oncolytic effects or toxicity for some anticancer drugs. This review has exemplified differences in the clinical pharmacology of several anticancer drugs, when children are compared to adults. Such age-related differences in the pharmacokinetics and pharmacodynamics of these drugs, together with biologic differences between pediatric and adult cancers, provide the rationale for systematically conducting pediatric phase I through IV studies of anticancer drugs and denote the risks of relying on adult trials to identify new therapeutic strategies for childhood cancers.