Inhibition of the sodium–glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney has a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. SGLT2 inhibitors are chiefly used in type 2 diabetes for glucose control, achieving reductions in HbA_1c of 7–10 mmol/mol (0.6–0.9%) when compared with placebo. This glucose-lowering activity is proportional to the ambient glucose concentration and glomerular filtration of this glucose, so may be greater in those with poor glycaemic control and/or hyperfiltration at baseline. Equally, the glucose-lowering effects of SGLT2 inhibitors are attenuated in individuals without diabetes and those with a reduced eGFR. However, unlike the glucose-lowering effects of SGLT2 inhibitors, the spill-over of sodium and glucose beyond the proximal nephron following SGLT2 inhibition triggers dynamic and reversible realignment of energy metabolism, renal filtration and plasma volume without relying on losses into the urine. In addition, these processes are observed in the absence of significant glucosuria or ongoing natriuresis. In the long term, the resetting of energy/salt/water physiology following SGLT2 inhibition has an impact, not only on adiposity, renal function and blood pressure control, but also on the health and survival of patients with type 2 diabetes. A better understanding of the precise biology underlying the acute actions of SGLT2 inhibitors in the kidney and how they are communicated to the rest of the body will likely lead to improved therapeutics that augment similar pathways in individuals with, or even without, diabetes to achieve additional benefits.