The brain is the organ primarily affected by elevated phenylalanine (Phe) in the disease phenylketonuria (PKU). The hallmark neuropathology of both the untreated and treated PKU brains is hypomyelination or demyelination or both. Because cognitive deficits are present in untreated and treated individuals, the link between the observed neuropathology and cognitive deficits is important to ascertain. Two current models of the molecular events underlying the cognitive deficits are presented. The first model is based on the hypothesis that cognitive deficits in individuals with PKU result from a deficiency of the neurotransmitter dopamine. Decreased levels of tyrosine in the PKU brain are believed to cause the low levels of dopamine. The possible connections between reduced dopamine levels and the observed myelin deficits are presented. However, as discussed, the link between the two remains elusive. The second model is based on the hypothesis that the primary insult to the PKU brain is loss of myelin and that this secondarily leads to neuronal dysfunction. The function of myelin is reviewed, including evidence showing that myelin and the axon communicate with one another to form a functional unit. Because the ability of the axon to conduct action potentials at normal speed is compromised when myelin is not formed or is lost, the latter model has the capacity to account for both abnormalities and cognitive deficits. Current studies characterizing the neuropathology of the recently developed genetic mouse model for PKU, the PAH enu2 mouse, are reviewed. Preliminary evidence is summarized that indicates that Phe specifically inhibits cholesterol metabolism in the oligodendrocyte, the cell that forms myelin in the brain. Finally, areas of future, high-priority research are outlined.