Hemoglobin, the critical protein in the delivery of oxygen to mammalian tissues, is poorly adaptated to that function. This awkward situation is remedied by the presence in the red cell of 5 to 7 mM 2,3 DPG, which binds to Hb competitively with oxygen and reduces oxygen affinity. How the levels of 2,3 DPG in the red cell are regulated is an important question that has not yet been fully answered. The best established correlation with 2,3 DPG concentration in red cells is the activity of the enzyme pyruvate kinase. Inverse relationship between 2,3 DPG content and pyruvate kinase activity is the result of two conditions within the erythrocyte. The metabolites between FBP and PEP are in a state of quasi equilibrum because the activity of pyruvate kinase is so much lower than the activities of other enzymes in the pathway. Furthermore, pyruvate kinase operates, in vivo at a PEP concentration well below the Km concentration. In consequence, an increase in the glycolytic rate or inhibition of pyruvate kinase causes an increase in PEP concentration. Increases in PEP levels lead to increases in the levels of 2,3 DPG, and hence to increases in the level of 2,3 DPG via the 2,3 DPG synthase reaction. This relationship is demonstrated by the frequent occurrence of elevated levels of 2,3 DPG in pyruvate kinase deficient erythorcytes and by the decreased levels of 2,3 DPG and PEP which are observed in erythrocytes containing a pyruvate kinase with abnormally high activity at low PEP levels. It is thus clear that control of pyruvate kinase activity is a means to the control of oxygen delivery by the erythrocyte. It remains to be discovered wherther any of the observed variations in human PK activity are due to reversible posttranslational modification and whether the potential for control of oxygen delivery via changes in pyruvate kinase activity is made use of the normal human adult. The availability of human full length cDNA for PK should accelerate our inderstanding of he structure- -function relationships of PK deficiency and enhance the possibility of gene therapy for seriously affected PK patients.