1. The change in energy metabolism of red blood cells from the newborn calf to adult cow was examined utilizing a number of metabolic substrates including glyceraldehyde, dihydroxyacetone, ribose, glucose, adenosine and inosine. 2. All of these substrates are utilizes by the newborn calf cells to a varying degree. With glyceraldehyde, dihydroxyacetone or glucose as a substrate, lactate is formed at a rate of 2-3 mumol/ml cells per h. As in other species, ribose utilization depends on substrate concentration, with an optimum of 3 mM ribose yielding lactate 1-1.5 mumol/ml cells per h in the calf cells. 3. In sharp contrast, adult cow red blood cells lost the bulk of the postnatal metabolic substrate affinities except for glyceraldehyde and glucose which are consumed at less than half of the rate at birth. 4. While the transition of the metabolic properties from the newborn to the adult state takes place within 2 to 3 months after birth, the red blood cells produced shortly after birth have already assumed the metabolic machinery characteristic to the adult cells. 5. Even though adenosine in itself is a poor substrate in producing lactate, a net synthesis of ATP from adenosine can take place in both calf and cow cells provided that an alternate carbon source such as glyceraldehyde, dihydroxyacetone or glucose is given. 6. Of the test substrates, glucose is the only substrate for the adult cow cells exhibiting a greater than 50% increase in utilization by exogenously added adenine. By contrast, the calf cell is affected to a much lesser extent. The possible in vivo regulatory metabolic role of certain purine and pyrimidine compounds unique to the adult stage of this species is discussed.