It is now widely accepted that the changes in the molecular milieu of the human central nervous system (CNS) that precipitate frank psychiatric illness is because of the impact of susceptibility genes and as yet to be identified environmental stressors (Tsuang Biol Psych 2000, 47 210). Therefore, the demonstration of altered levels of apolipoprotein E (Dean et al. Bio Psych 2003, 54 616–622; Digney et al. Biol Psych 2005, 57 711–715) in the CNS from subjects with schizophrenia and bipolar 1 disorder suggested that this important glial-derived protein could be involved in the pathology of these disorders. Moreover, treating rats with haloperidol decreases frontal cortical apolipoprotein E (Dean et al. Bio Psych 2003, 54 616–622) suggesting that regulating apolipoprotein E might be a mechanism by which antipsychotic drugs could achieve therapeutic outcomes. Our data on haloperidol, which presumably affects apolipoprotein E levels by blocking dopaminergic activity, also added to studies showing that neurotransmitters such as serotonin, acetylcholine and glutamate (Deecher et al. J Neurosci Res 1993, 35 246–256; Andre et al. Euro J Neurosci 1994, 6 1702–1709; Gallo et al. J Neurochem 1987, 14 1801–1809) (all important in the pathology of psychiatric disease (Dean PMJ 2002, 78 142–148; World J Biol Psychaitr 2002, 3 125–132) can affect astrocytic function and thus apoE expression. Combining studies on apolipoprotein E with many of studies showing changes in neuronal-derived proteins in schizophrenia and bipolar disorder (Dean Postgrad Med J 2002, 78 142–148, World J Biol Psychaitr 2002, 3 125–132), it can be proposed that changes in tripartite synaptic function, the matrix involving pre- and postsynaptic neurons and associated glia, are altered in the CNS of some subjects with psychiatric illnesses. Evidence to support this hypothesis will be reviewed and potential mechanism of action and symptom outcomes will be discussed.