This paper reviews some important recent findings on the molecular biology of the peritoneal membrane. It attempts to correlate in vitro and in vivo experimental results with the possible clinical consequences. The most common functional alteration during long-term CAPD is increased peritoneal small-solute transport rate, resulting in impaired ultrafiltration and decreased dialysis efficiency. This contribution first discusses the most relevant advances in the biochemistry and molecular biology of the peritoneal membrane following peritonitis and as consequence of the continuous exposure to unphysiological dialysis fluids. In a second part the preliminary experimental and clinical experience with more biocompatible fluids is summarized. The most relevant structural and functional alterations of the membrane following repeated peritonitis is the consequence of the response of the peritoneum to infective organisms involving the inflammatory cytokines and the interaction between membrane resident cell populations: macrophages, mesothelial cells and fibroblasts. In this setting, human biopsy studies and animal experiments have identified an increase in the peritoneal-associated vasculature, which seems to be the primary cause of increased solute transport. The structural and functional alterations in the membrane in long-term peritoneal dialysis are thought to be the consequence of the toxicity of glucose, either directly or indirectly through the generation of glucose degradation products or the formation of advanced glycation end-products. In particular, an important role for vascular endothelial growth factor and nitric oxide as downstream mediators of the alterations has been suggested. Finally, the last part of this paper reviews the actual and future research aimed at an amelioration of the biocompatibility of the dialysis fluids. Replacing glucose by other osmotic agents, changing the sterilization process, replacing the lactate buffer by bicarbonate, blocking the formation of reactive carbonyl products and of the neoangiogenesis are the most promising changes to enhance the biocompatibility. Finally, gene therapy may in the future have an important contribution. Ex vivo gene therapy involves harvesting peritoneum samples to isolate mesothelial cells that will be genetically modified before re-implantation into the peritoneal cavity.