Both irinotecan (CPT-11, Camptosar) and epirubicin (Ellence) are significant chemotherapeutic agents that are used in the management of many different cancers. Each agent works through the inhibition of topoisomerases, and inhibition of topoisomerases I and II may possibly result in significant clinical synergy. This phase I clinical study represents an investigation of the first combination of irinotecan and epirubicin in patients with advanced cancer. Standard phase I eligibility was utilized, and recruitment proceeded in cohorts of three with escalating doses of irinotecan and epirubicin. The treatments were given on days 1 and 8 of a 28-day cycle. Our initial cohort of patients developed significant myelosuppression that required a modification in the initial dose-escalation scheme, and accrual to these lower doses is ongoing. Evidence of clinical activity has been observed. Accrual will continue until the maximum tolerated dose can be determined. Other schedules of the combination of irinotecan and epirubicin should be explored.