Uraemic syndrome (also known as uremic syndrome) in patients with advanced chronic kidney disease involves the accumulation in plasma of small-molecule uraemic solutes and uraemic toxins (also known as uremic toxins), dysfunction of multiple organs and dysbiosis of the gut microbiota. As such, uraemic syndrome can be viewed as a disease of perturbed inter-organ and inter-organism (host–microbiota) communication. Multiple biological pathways are affected, including those controlled by solute carrier (SLC) and ATP-binding cassette (ABC) transporters and drug-metabolizing enzymes, many of which are also involved in drug absorption, distribution, metabolism and elimination (ADME). The remote sensing and signalling hypothesis identifies SLC and ABC transporter-mediated communication between organs and/or between the host and gut microbiota as key to the homeostasis of metabolites, antioxidants, signalling molecules, microbiota-derived products and dietary components in body tissues and fluid compartments. Thus, this hypothesis provides a useful perspective on the pathobiology of uraemic syndrome. Pathways considered central to drug ADME might be particularly important for the body’s attempts to restore homeostasis, including the correction of disturbances due to kidney injury and the accumulation of uraemic solutes and toxins. This Review discusses how the remote sensing and signalling hypothesis helps to provide a systems-level understanding of aspects of uraemia that could lead to novel approaches to its treatment.