There now exists a significant amount of evidence from both animal and human studies that commercially-available dialysis solutions result in the changes of the peritoneal barrier. Mesothelial cells undergo an epithelial-to-mesenchymal transition after less than one year of dialysis. After more than 6 years of peritoneal dialysis, there is extensive fibrosis and vasculopathy in the submesothelial compact zone. Clinical studies demonstrate that the structural changes apparently correlate with alterations in transport function and progressive ultrafiltration failure. The possible mechanisms of inflammation include macrophage peroxide production, acidic dialysis solutions, glucose and its degradation products, the presence of a foreign body, and the integrated signaling of the chemokine-cytokine cascade of the peritoneal cellular immune response in conjunction with biofilm on the peritoneal catheter. Basic and translational research efforts are discussed to portray our current knowledge in this area and to outline the remaining questions.