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The dialysis disequilibrium syndrome is a rare but serious complication of hemodialysis. Despite the fact that maintenance hemodialysis has been a routine procedure for over 50 years, this syndrome remains poorly understood. The signs and symptoms vary widely from restlessness and headache to coma and death. While cerebral edema and increased intracranial pressure are the primary contributing factors to this syndrome and are the target of therapy, the precise mechanisms for their development remain elusive. Treatment of this syndrome once it has developed is rarely successful. Thus, measures to avoid its development are crucial. In this review, we will examine the pathophysiology of this syndrome and discuss the factors to consider in avoiding its development.