Cardiovascular disease is the most common cause of the greatly elevated rates of mortality characteristic of patients undergoing maintenance hemodialysis. This article is an attempt to describe the complex and evolving features of cardiac disease routinely encountered in HD patients. Furthermore, by trying to appreciate the pathophysiological drivers, and the crucial interaction with the HD treatment itself, this article seeks to define cardiac disease in this setting (HD-associated cardiomyopathy) as a unique and complex entity. By understanding the phenotype and basis of HD-associated cardiomyopathy, we can develop an evolved understanding of the dominant processes involved in its development and offer up dialysis-based interventions specifically designed to mitigate the cumulative ischemic insults consequent to conventional HD treatment. This article explores the justification of this approach and recent evidence of its efficacy.