During peritoneal dialysis, peritoneal cells are repeatedly exposed to a non-physiologic hypertonic environment with high glucose content and low pH. Current sterile dialysis solutions cause inflammation in the submesothelial compact zone, leading to fibrosis, angiogenesis, and, eventually, ultrafiltration failure. Although the normal interstitium separates the peritoneal microvasculature from the dialysis fluid and makes transperitoneal transport less efficient, changes in the submesothelial compact zone can result in progressive increases in solute transfer and ultrafiltration diminution. This peritoneal dysfunction will further be amplified with the development of an epithelial-to-mesenchymal transition of mesothelial cells and dissipation of the osmotic driving force through the increased area and solute transport that accompany neoangiogenesis of the submesothelial microvasculature. The alteration of the peritoneal membrane can be further aggravated by peritonitis, advanced glycation end-products, and glucose degradation products. Furthermore, new data are emerging to support a proinflammatory role for peritoneal adipocytes.