The blood-brain barrier (BBB) regulates the entry of proteins, electrolytes, vitamins, minerals, fatty acids, peptides, and medicines into the CNS. The regulation mechanisms mature with age and can be altered by disease. The primary function of the blood brain barrier is threefold: 1. inhibition of intercellular passage of molecules by tight junctions between endothelial cells; 2. inhibition of intracellular passage because of inherent low pinocytic activity; and 3. specific transport systems within endothelial cells that actively transport nutrients into the brain while toxins are actively transported out. Adult BBB permeability is reached by two months of age. Physical and enzymatic barrier functions within tight junctions exist to maintain brain homeostasis in children. Thus, drug metabolizing proteins actively metabolize lipophilic drugs such as fentanyl and/or promote drug efflux. However, barbiturates and morphine penetrate the blood-brain barrier in neonates and are in essence “trapped” when compared to adults. Drug absorption Oral medications are a commonly used form in children. Neonates have a higher gastric pH, slower gastric and intestinal motility, slower intestinal drug transport, and limited bacterial flora. Therefore neonates, infants, and small children may have a slower onset of action of per oral (PO) medications. Intramuscular drugs have a higher bioavailability in neonates and infants due to increased muscle capillaries in this vessel-rich group. Immature livers can lead to higher bioavailability in rectally administered medications that undergo first-pass metabolism. Rectal drugs may also be expelled more quickly. Thinner skin, large surface area, and increased perfusion increase the bioavailability of transdermal medications.