Peritoneal dialysis (PD) is associated with functional and structural changes of the peritoneal membrane. In this review we describe factors contributing to peritoneal tissue remodeling, including uremia, peritonitis, volume loading, the presence of a catheter, and the PD fluid itself. These factors initiate recruitment and activation of peritoneal cells such as macrophages and mast cells, as well as activation of peritoneal cells, including mesothelial cells, fibroblasts, and endothelial cells. We provide an overview of cytokines, growth factors, and other mediators involved in PD-associated changes. Activation of downstream pathways of cellular modulators can induce peritoneal tissue remodeling, leading to ultrafiltration loss. Identification of molecular pathways, cells, and cytokines involved in the development of angiogenesis, fibrosis, and membrane failure may lead to innovative therapeutic strategies that can protect the peritoneal membrane from the consequences of long-term PD.