Several lines of evidence support the notion that a substantial reorganization of cortical connections, involving a programmed synaptic pruning, takes place during adolescence in humans. A review of neurobiological abnormalities in schizophrenia indicates that the neurobiological parameters that undergo peripubertal regressive changes may be abnormal in this disorder. An excessive pruning of the prefrontal corticocortical, and corticosubcortical synapses, perhaps involving the excitatory glutamatergic inputs to pyramidal neurons, may underlie schizophrenia. A reciprocal failure of pruning in certain subcortical structures, such as lenticular nuclei, may also occur. Several developmental trajectories, related to early brain insults as well as genetic factors affecting postnatal neurodevelopment, could lead to the illness. These models would have heuristic value and may be consistent with several known facts of the schizophrenic illness, such as its onset in adolescence and the gender differences in its onset and natural course. The relationship between these models and other etiological models of schizophrenia are summarized and approaches to test relevant hypotheses are discussed.