Donation of organs after circulatory death (DCD) is re-emerging as an important source of organs for transplantation worldwide, and in the United Kingdom DCD donors comprise 39% of all deceased organ donors. However, organs from DCD organ donors work less well after transplantation than those from brainstem dead organ donors. This increased prevalence of initial poor function, despite good performance in the donor prior to death, suggests that changes in donor physiology during the agonal phase, together with the subsequent period of warm ischaemia, may be responsible for the differences seen in organ function. Although donated organs and warm ischaemia have been extensively studied, the physiological changes occurring in the DCD organ donor during the dying process remain poorly understood and ill-defined mechanistically. In this thesis, the physiology of the DCD donor between withdrawal of life supporting treatment and death is examined in detail for the first time in human donors. Extensive public and patient engagement work demonstrate public support for research in the potential organ donor, and this finding is borne out by focus group work. Examination of a cohort of DCD donors demonstrated previously undocumented patterns of physiology, which have significant implications for the function of transplanted organs. A key finding is the lack of concordance between arterial oxygen saturations when measured by pulse oximetry and by arterial blood gas (ABG) analysis. This has demonstrated that saturation assessment by ABG analysis document oxygen saturation being above generally accepted minimal levels for up to 40 minutes longer in donors during the maximum accepted agonal period of 240 minutes. I also present evidence of cardiothoracic organ retrieval decisions based on saturations which have led to potentially transplantable organs being declined. An investigation of markers of anaerobic metabolism in the potential donors who do proceed to DCD revealed correlations between hypotension, oxygen delivery and oxygen extraction ratio, and elevated lactate levels. Further examination of the relationship between oxygen delivery and systolic blood pressure in this cohort demonstrate that blood pressure is conserved in many patients beyond the point at which oxygen delivery falls to critical levels. This finding suggests current organ retrieval decisions based on systolic blood pressure may not be best practice or evidence based. These physiological changes during the agonal period of circulatory death are accompanied by cognate changes in human donor biology that have not previously been documented in DCD donors. These include evidence of sympathetic stimulation (elevated catecholamine levels), activation of the hypothalamic-pituitary-adrenal axis (with cortisol levels elevated in a subgroup surviving over 30 minutes after withdrawal of life support), and immune activation (changes in IL-6 and TNF- that mirror those seen in animal models of DCD donation). In conclusion, this thesis demonstrates physiological changes not previously recorded in human subjects in a cohort of DCD organ donors undergoing circulatory death. These changes have implications for the management of potential organ donors undergoing circulatory death, and impact on the organs they donate. Modulation of these changes represent a therapeutic target, successful modulation of which could translate to improved donation rates and organ transplantation outcomes.