The naturally occurring substance phlorizin has long been recognized to block the reabsorption of glucose from the glomerular ultrafiltrate into the systemic circulation. The poor oral bioavailability and adverse effects associated with this agent, however, have prevented its use in clinical practice and restricted its use to that of a physiological tool. The development of novel agents that are able to block the principal glucose transporter in the kidney has allowed the inhibition of renal glucose reabsorption to be re-evaluated as a therapeutic tool in patients with diabetes mellitus. This Perspectives article summarizes current knowledge pertaining to glucose transport in the kidney and describes the evidence regarding glucose transport blockade as a novel target for the management of hyperglycemia in the context of existing treatment strategies.