Streptozotocin is an antibiotic with antitumor properties. It has been reported to be diabetogenic in dogs, monkeys, hamsters, rats, and mice. Rabbits and guinea pigs were found to be resistant to the diabetogenic action of streptozotocin. Resistance in these species was not related to impaired ability to maintain adequate serum concentrations of the drug. Streptozotocin incubated with rabbit serum and liver homogenate maintained its diabelogenic properties when injected in the rat. Liver and pancreas homogenates of the resistant species did not metabolize the drug in vitro as determined spectrophotometrically. It is postulated that the diabetogenic action of streptozotocin may be related to its ability to impair NAD synthesis. It is postulated that the drug apparently blocks the synthesis of NAD from nicotinamide but has no effect on the synthesis of NAD from nicotinic acid, the pathway which may be preferentially employed by rabbits and guinea pigs.