Cancer is a major cause of global mortality, affecting both affluent and developing countries. Many cancer patients experience reduced life expectancy and die with metastatic disease. However, the precise causes of mortality and deterioration before death remain poorly understood, posing challenges for developing new treatments to improve quality and extend life for late-stage cancer patients. This Roadmap reviews the proximal causes of mortality in cancer patients, discusses the interconnections between mechanisms contributing to mortality, and proposes new avenues for data collection, research, and treatment development. It highlights the complexity of cancer mortality, which involves multiple interconnected systems and factors, including acute events like vascular/coagulation/cardiac failure, organ displacement or obstruction, infections, paraneoplastic syndromes, therapy-induced toxicity, and underlying causes such as immune and haematopoietic system dysfunction, nervous system impairment, and metabolic changes like cachexia. The interplay between these factors can lead to organ failure, sepsis, and other life-threatening conditions. Understanding these mechanisms is crucial for improving patient care, optimizing treatment strategies, and enhancing quality of life. The Roadmap also emphasizes the importance of improved records, detailed observational studies, and more relevant model systems to better understand cancer mortality. It concludes that cancer mortality is influenced by a complex interplay of factors, and that understanding these mechanisms can lead to better strategies for managing advanced cancer and improving patient outcomes.Cancer is a major cause of global mortality, affecting both affluent and developing countries. Many cancer patients experience reduced life expectancy and die with metastatic disease. However, the precise causes of mortality and deterioration before death remain poorly understood, posing challenges for developing new treatments to improve quality and extend life for late-stage cancer patients. This Roadmap reviews the proximal causes of mortality in cancer patients, discusses the interconnections between mechanisms contributing to mortality, and proposes new avenues for data collection, research, and treatment development. It highlights the complexity of cancer mortality, which involves multiple interconnected systems and factors, including acute events like vascular/coagulation/cardiac failure, organ displacement or obstruction, infections, paraneoplastic syndromes, therapy-induced toxicity, and underlying causes such as immune and haematopoietic system dysfunction, nervous system impairment, and metabolic changes like cachexia. The interplay between these factors can lead to organ failure, sepsis, and other life-threatening conditions. Understanding these mechanisms is crucial for improving patient care, optimizing treatment strategies, and enhancing quality of life. The Roadmap also emphasizes the importance of improved records, detailed observational studies, and more relevant model systems to better understand cancer mortality. It concludes that cancer mortality is influenced by a complex interplay of factors, and that understanding these mechanisms can lead to better strategies for managing advanced cancer and improving patient outcomes.