The peptide transporter PEPT2 mediates cellular uptake of di- and tripeptides driven by an inwardly directed electrochemical proton gradient. In mammals PEPT2 is found in a variety of organs such as kidney, lung, brain, enteric nervous system, and mammary gland. Highest expression levels are observed in renal proximal tubules where PEPT2 contributes to reabsorption of filtered di- and tripeptides. To assess the physiological importance of the transporter in overall metabolism, we have generated a Pept2-/- mouse line that lacks a functional PEPT2 protein. Here we present data on body weight, organ weights, and blood pressure. Mice were then fed diets containing either 10, 20, or 30% (w/w) protein, and food and water intake rates as well as plasma and urine parameters were determined. In spite of PEPT2 expression in a variety of tissues, only subtle phenotypic changes were observed. Male PEPT2 null mice displayed lower bodyweight and lower relative heart weight, whereas, relative kidney weight was lower in female Pept2-/- mice. No differences were found in blood pressure. When fed diets with different protein contents, Pept2-/- mice adapted food intake to dietary protein content with higher consumption rates on low protein and reduced food intake rates on the high protein diet.