Glucose has served well as the prototypical osmotic agent in peritoneal dialysis for more than 2 decades, because it affords many of the characteristics required of a safe and effective osmotic agent. The disadvantages of glucose include its rapid dissipation from the peritoneum and its resulting limited UF efficiency capacity in high and high-average transporters, the associated metabolic response to absorbed glucose in all patients, and the local effects of glucose, glucose degradation products, and hyperosmolality on peritoneal membrane structure and function. This paper briefly reviews the salient elements of glucotoxicity associated with conventional glucose-based peritoneal dialysis (PD) solution use, and then discusses emerging clinical benefits of newer nonglucose PD solutions. Potential future strategies designed to abrogate glucose-associated toxicity are then reviewed. These approaches include bimodal long-dwell solutions, nonglucose crystalloid osmotic agent mixtures, and administration of pharmacologically active agents.