ABOUT 180 g of glucose are filtered daily in the glomeruli of the kidneys in a healthy normoglycemic subject, which is equivalent to approximately one third of the total energy consumed by the human body in a day. Most of the glucose entering the tubular system is reabsorbed along the nephron segments, primarily in the proximal tubule, such that urine is almost free of glucose. This is different in diabetes, where the filtered glucose exceeds the transport capacity of the tubular system for glucose and glucosuria occurs. On the basis of transport studies in membrane vesicles and analyses of mRNA expression in isolated nephron segments of rat and rabbit kidneys, performed largely between 1981 and 1995, the concept has been established that the bulk of tubular glucose uptake across the apical membrane occurs in the early proximal tubule and is mediated by the low-affinity/high-capacity Na -glucose cotransporter SGLT2 (SLC5A2); in comparison, the high-affinity/low-capacity SGLT1 (SLC5A1) is thought to “clean up” most of the remaining luminal glucose in further distal parts of the proximal tubule (2, 4, 6, 7, 9, 11, 18–21)(see Fig. 1). With newly available specific antibodies, recent studies directly document specific expression of brush border membrane SGLT2 in early proximal tubule and SGLT1 in later sections of the proximal tubule (1, 14). Much of the evidence for the relative quantitative contribution of these proteins to renal glucose reabsorption in human derives from the phenotype of subjects carrying gene mutations. Whereas mutations in SGLT1 are associated with intestinal glucose malabsorption with little or no glucosuria, individuals with gene mutations in SGLT2 have persistent renal glucosuria (10). Interest in SGLTs has recently been sparked by the development of a novel antidiabetic therapeutic approach, namely, the selective pharmacological inhibition of SGLT2, which inhibits renal reabsorption of glucose, thereby increasing its urinary excretion and reducing plasma glucose levels (17). During diabetes, excess glucose uptake via SGLTs may contribute to the glucose toxicity in the diabetic kidney. Moreover, an increase in SGLT-mediated sodium/ glucose reabsorption has been implicated in the enhanced proximal tubular sodium reabsorption in the diabetic kidney which lowers luminal NaCl concentration at the macula densa and, because of the normal physiology of tubuloglomerular feedback, can contribute to glomerular hyperfiltration observed in early diabetes (15). Thus, SGLT2 inhibitors may also have the potential to reduce the glucose toxicity and hyperfiltration observed in the diabetic kidney. Despite this new clinical interest in renal glucose handling, surprisingly little information has been available on the specific characteristics of human SGLT2 and SGLT1. The timely study by Hummel and colleagues (5) in this issue of American Journal of Physiology-Cell Physiology builds on the previous pioneering studies of Wright’s group in the field Address for reprint requests and other correspondence: V. Vallon, Depts. of Medicine and Pharmacology, Univ. of California San Diego and VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161 (e-mail: firstname.lastname@example.org).