After birth, continuous transplacental transfer of glucose is interrupted. Neonates have to provide brain and vital organs with sufficient glucose. In term newborn infants, this is accomplished through well-coordinated hormonal and metabolic adaptive changes. During the first week of life, preterm infants are at high risk of abnormal glucose homeostasis. They are at risk of hypoglycemia due to limited glycogen and fat stores that should have occurred in the third trimester. Continuous glucose infusion is always required soon after birth to maintain the glucose level. However, under such conditions, many preterm infants develop hyperglycemia. Defective islet β-cell processing of proinsulin is likely related to hyperglycemia. There is also evidence that preterm infants are partially resistant to insulin. By contrast with adults, hepatic glucose production is not suppressed during parenteral glucose infusion. Exogenous insulin infusion partially reduces endogenous glucose production in preterm newborn infants. This treatment is efficient and safe when used with caution. More research is needed to understand the specificity of glucose homeostasis in preterm infants and to evaluate the long-term consequences of metabolic and nutritional support during early life.