While schizophrenia has long been recognized as a syndrome, no strong biological basis for segregating the diseases within that syndrome has been elucidated. One of the defining outcomes of disease is changes in the biochemical pathways affected by the disorder. Such changes would be predicted to alter levels of critical proteins in these disease-specific pathway changes. Two-dimensional (2D) electrophoresis now provides the opportunity to identify changes in the levels of multiple proteins in complex biological symptoms and therefore offers the opportunity to identify disease-specific protein footprints in tissue affected by different diseases. This approach has already been used to identify proteins that are affected in tumors and hence lead to specific targets for drugs to treat different forms of cancer. In a similar approach, 2D electrophoresis is being carried out using postmortem central nervous system (CNS) from a large cohort of subjects with schizophrenia and tissue from the same CNS region of subjects with no history of psychiatric or neurological disease. We have modified the approach to 2D electrophoresis so that the analyses will measure the levels of over 10 000 proteins in each tissue sample. In collaboration with the Centre for Mathematics and Statistics of Complex Systems, we are now analyzing our 2D gels to identify grouping of differential protein expression patterns that might define different illnesses within the syndrome of schizophrenia. In this presentation, a proof of principal study to differentiating schizophrenia and bipolar disorder will be presented.