Kidney blood flow and glomerular filtration rate (GFR) are maintained relatively constant by hormonal influences and by efficient autoregulation. However, the kidney remains at risk for ischemia and acute kidney injury. Increases in kidney blood flow cause parallel increments in GFR, thereby dictating tubular reabsorption and increased oxygen/metabolic demands. Coordination between kidney blood flow and GFR with tubular reabsorption is maintained by the tubuloglomerular feedback (TGF) system whereby delivery of NaCl to the macula densa varies inversely with nephron GFR. Metabolic products, ATP and adenosine, are the mediators of TGF via afferent arteriolar vasoconstriction, and nitric oxide; COX-2 products and angiotensin II are modulators of acute TGF responses and temporal adaptation of TGF. Oxygen requirements and metabolic efficiency of Na transport in the kidney are significant variables that are regulated by both mediators and modulators of TGF. These metabolic and hormonal substances efficiently regulate both kidney supply and demand.