Current conventional hemodialysis (HD) is largely an industrialized process, with inadequate attention to the role that the dialysis treatment itself may play in the development and promulgation of uremic related disease states. HD is capable of exerting significant recurrent systemic circulatory stress. There is already an appreciation that this may be important in the development of cardiac disease, but it appears that this systemic insult is capable of resulting in perfusion-dependent injury of a wide range of vulnerable vascular beds. These include gut, brain, and potentially the kidney. This predominantly hemodynamic injury can therefore result a mixed picture of direct perfusion-related injury, local/systemic inflammation, and potentiation of further cycles of injury. This article aims to put forward a pathophysiological paradigm that places dialysis-induced acute injury at the center of much of the observed disease burden in HD patients.