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Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a multimodal treatment approach combining surgical interventions of varying extent with administration of heated cytostatic drugs flushed through the abdominal cavity. Hitherto, this treatment has been popular for peritoneal metastasis (PM), e.g. from colorectal cancer (CRC). Recent randomized controlled trials (RCT) question the benefit of HIPEC in its present form for CRC treatment and raise fundamental issues, eliciting discussions and expert statements regarding HIPEC relevance and interpretation of these results. Unfortunately, such discussions have to remain uninformed, due to the lacking publication of crucial peer reviewed RCT results. Novel basic research aware of HIPEC futility suggests there may be systematic limitations. Innovative modelling approaches for HIPEC may shed light on the reasons for therapeutic failure of frequently used drugs and may lead the way to select better alternatives and/or more rational approaches for the design of HIPEC procedures (e.g. regarding exposure time or temperature). Available evidence strongly supports the notion that CRS is the mainstay for the treatment effects observed in PM from CRC. Unfortunately, HIPEC has become a surrogate for surgical expertise in the field and optimal surgery may therefore outweigh the potentially harmful effects of HIPEC treatment, particularly in lieu of modern systemic chemotherapies. The current situation which frequently is assumed to be deadlocked should be regarded as a challenge to investigate HIPEC with well-designed prospective clinical trials, potentially even constituting an opportunity for introducing innovative trial designs that solve the multifaceted issues of a very heterogeneous treatment approach.