The uraemic syndrome is a complex clinical picture developing in the advanced stages of chronic kidney disease, resulting in a myriad of complications and a high early mortality. This picture is to a significant extent defined by retention of metabolites and peptides that with a preserved kidney function are excreted or degraded by the kidneys. In as far as those solutes have a negative biological/biochemical impact, they are called uraemic toxins. Here, we describe the historical evolution of the scientific knowledge about uraemic toxins and the role played in this process by the European Uraemic Toxin Work Group (EUTox) during the last two decades. The earliest knowledge about a uraemic toxin goes back to the early 17th century when the existence of what would later be named as urea was recognized. It took about two further centuries to better define the role of urea and its link to kidney failure, and one more century to identify the relevance of post-translational modifications caused by urea such as carbamoylation. The knowledge progressively extended, especially from 1980 on, by the identification of more and more toxins and their adverse biological/biochemical impact. Progress of knowledge was paralleled and impacted by evolution of dialysis strategies. The last two decades, when insights grew exponentially, coincide with the foundation and activity of EUTox. In the final section, we summarize the role and accomplishments of EUTox and the part it is likely to play in future action, which should be organized around focus points like biomarker and potential target identification, intestinal generation, toxicity mechanisms and their correction, kidney and extracorporeal removal, patient-oriented outcomes and toxin characteristics in acute kidney injury and transplantation.