Background: The uremic syndrome is characterized by a complex clinical picture, whereby the function of multiple organ systems is affected by the retention of a host of solutes. Recent research of the last decade has helped to unravel multiple pathophysiologic mechanisms and to identify as yet unknown responsible compounds. Methods: The literature was screened to appreciate which compounds play the most important pathophysiologic role. Results: The picture that ensues is that the main role is played by molecules which are so-called ‘difficult to remove by dialysis’. The knowledge of uremic toxicity is still far from complete and we need extra information about responsible compounds and mechanisms, eventually leading to a classification of the most important culprits, to allow the development of efficient removal strategies and of pharmacologic methods to counteract pathophysiologic mechanisms. Conclusions: Uremic retention is a complex phenomenon and the most toxic compounds are difficult to remove by dialysis. Furthermore, our knowledge of the responsible pathways is still incomplete, and needs to be extended to develop new and more efficient treatment strategies.

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