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A healthy and functional peritoneal membrane is key to achieving sufficient ultrafiltration and restoring fluid balance, a major component of high-quality prescription in patients treated with peritoneal dialysis (PD). Variability in membrane function at the start of PD or changes over time on treatment influence dialysis prescription and outcomes, and dysfunction of the peritoneal membrane contributes to fluid overload and associated complications. In this review, we summarize the current knowledge about the structure, function, and pathophysiology of the peritoneal membrane with a focus on clinical implications for patient-centered care. We also discuss the molecular and genetic mechanisms of solute and water transport across the peritoneal membrane, including the role of aquaporin water channels in crystalloid versus colloid osmosis; why and how to assess membrane function using peritoneal equilibration tests; the etiologies of membrane dysfunction and their specific management; and the effect of genetic variation on membrane function and outcomes in patients treated with PD. This review also identifies the gaps in current knowledge and perspectives for future research to improve our understanding of the peritoneal membrane and, ultimately, the care of patients treated with PD., (Copyright © 2023 by the American Society of Nephrology.)