Abnormalities of cognitive function and high levels of depression incidence are characteristic of hemodialysis patients. Although previously attributed to the humoral effects of uremia, it is becoming increasingly appreciated that many elements of the overall disease state in CKD patients contribute to functional disturbances and physical brain injury. These factors range from those associated with the underlying primary diseases (cardiovascular, diabetes etc.) to those specifically associated with the requirement for dialysis (including consequences of the hemodialysis process itself). They are, however, predominantly ischemic threats to the integrity of brain tissue. These evolving insights are starting to allow nephrologists to appreciate the potential biological basis of dependency and depression in our patients, as well as develop and test new therapeutic approaches to this increasingly prevalent and important issue. This review aims to summarize the current understanding of brain injury in this setting, as well as examine recent advances being made in the modification of dialysis-associated brain injury.