Adenosine A1 and A2A receptor subtypes modulate metabolism in adult mammals. This study was designed to determine the role of these receptors in regulating plasma levels of insulin, glucose, and lactate in 20 chronically catheterized fetal sheep (>0.8 term). In normoxic fetuses (PaO2 ∼24 Torr), systemic blockade of A1 receptors with DPCPX ( n = 6) increased plasma concentrations of insulin, glucose, and lactate, but antagonism of A2A receptors with ZM-241385 ( n = 5) had no significant effects. Intravascular administration of adenosine ( n = 9) reduced insulin concentrations and elevated glucose and lactate levels. DPCPX ( n = 6) augmented the glycemic and lactatemic responses of adenosine. In contrast, ZM241385 ( n = 5) virtually abolished adenosine-induced hyperglycemia and hyperlactatemia. Isocapnic hypoxia (PaO2 ∼13 Torr) suppressed insulinemia and enhanced glycemia and lactatemia, but only the hyperglycemia was blunted by blockade of A1 ( n = 6) or A2A ( n = 6) receptors. We conclude that 1) endogenous adenosine via A1 receptors depresses plasma concentrations of insulin, glucose, and lactate; 2) exogenous adenosine via A2A receptors increases glucose and lactate levels, but these responses are dampened by stimulation of A1 receptors; and 3) hypoxia, which increases endogenous adenosine concentrations, induces hyperglycemia that is partly mediated by activation of A1 and A2A receptors. We predict that adenosine, via A1 receptors, facilitates at least 12% of glucose uptake and utilization in normoxic fetuses.