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In patients with tumors confined to the peritoneal cavity, there is established pharmacokinetic and tumor biology-related evidence that intraperitoneal drug administration is advantageous. Three large randomized trials in patients with stage III ovarian cancer who underwent optimal cytoreduction have demonstrated a significant survival benefit when intraperitoneal chemotherapy was added to systemic therapy. Although intraperitoneal therapy is associated with locoregional toxic effects, recent trials suggest that with some modification of the local delivery methods this approach is safe in 80% of patients in an ambulatory setting. Surgical cytoreduction immediately followed by intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) ensures intraperitoneal delivery of the drug to all peritoneal surfaces and the advantages of combined hyperthermia to be exploited. An increasing number of centers are initiating this multimodality therapy in ovarian cancer and colorectal cancer. Clearly, intraperitoneal drug delivery is an important adjunct to surgery and systemic chemotherapy in selected patients. The optimal drug, dose and schedule for intraperitoneal delivery, the exact role of added HIPEC compared with cytoreduction alone, and the potential role of HIPEC in ovarian cancer and peritoneal mesothelioma are still undefined. Several randomized controlled trials addressing these uncertainties have been initiated.