Physiological changes occurring perinatally and in the first month of life can affect the answer to a pharmacological treatment and the individual response to a drug in terms of efficacy and toxicity is highly variable in the neonatal population. Among potential causes for such variability, differences in drug metabolism may have a great impact. This article aims to review qualitative and quantitative differences in drug metabolizing enzymes in neonates, since both phase I and phase II metabolic pathways are immature at birth and subject to maturational changes in the first period of extrauterine life. Moreover, clinical implications will be discussed.