Healthy kidneys filter ~160 g of glucose per day (~30% of calorie intake). To prevent this energy from being lost, the proximal tubule avidly reabsorbs filtered glucose up to ~450 g/day, primarily by the sodium glucose cotransporter SGLT2 in the early proximal tubule. When SGLT2 is inhibited, the kidneys’ reabsorptive capacity for glucose declines to ~80 g/day, mediated by SGLT1 in the late proximal tubule, and glucose is spilled into the urine. SGLT2 inhibitors (SGLT2i) not only improve glycemic control in all stages of type 2 diabetes, but can protect the kidneys of patients with and without type 2 diabetes from failing. The basic idea for their therapeutic use is to lower the body’s glucose burden, but the rationale to protect the kidneys goes much further. The hypoglycemia risk of SGLT2i is low because they naturally stop working when the filtered glucose load falls to the reabsorption capacity of SGLT1, and they don’t otherwise interfere with metabolic counter regulation. Through glucosuria, SGLT2i induce a modest osmotic diuresis as well as a fasting-like response associated with lesser body fat and weight and a shift in substrate utilization from carbohydrates to lipids and ketone bodies, which serve as energy sources for many organs. Because SGLT2 reabsorbs Na along with glucose and is positively coupled to other transporters in proximal tubule brush border, like NHE3 and URAT1, SGLT2i are natriuretic, uricosuric, and antihypertensive. And, because they work in the proximal tubule, they increase delivery of fluid and NaCl to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure, which acutely lower glomerular pressure and filtration, thereby reducing the physical stress on the filtration barrier, the exposure to tubulotoxic substances, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity and improved mitochondrial function and autophagy, can reduce pro-inflammatory and pro-fibrotic signaling and preserve tubular function and GFR in the long-term. By shifting transport downstream, SGLT2i more equally distribute transport work along the nephron but may also simulate systemic hypoxia at the kidney outer medullary oxygen sensor and stimulate erythropoiesis, which improves oxygen delivery to kidneys and other organs. We are only beginning to understand the integrated kidney and body response to inhibiting SGLT2. Much needs to be learned including i) the effects on the inner workings of early proximal tubule cells, ii) the likely contrasting consequences on downstream segments that are exposed to more glucose, fluid and NaCl, iii) consequences of increasing macula densa glucose delivery, which is sensed by SGLT1, iv) glomerular hemodynamic effects via the efferent arteriole, and v) potential off-target effects of SGLT2i, which all hold potential for further clues how to protect the kidneys and heart. Moreover, can we identify transporters with characteristics similar to SGLT2 that can serve as new therapeutic targets to treat metabolic and kidney disease?