The authors discuss literature evidence on the possible dysfunctioning of HPA axis and the inflammatory response system (IRS) in schizophrenia in relation to a more comprehensive bio-pathogenetic hypothesis of the disorder and to the development of specific clinical patterns or 'core' schizophrenic symptoms, like those included in the so called negative/depressive dimension. The dysfunctions of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant brain areas like hippocampus and it could involve mainly the glutamatergic pathways (e.g. NMDA receptors). Moreover, these changes could have some predictive value for response to typical antipsychotics (specifically for negative symptoms and drug resistance) in schizophrenia. Finally, the differential activity of typical versus atypical antipsychotic compounds on the basic HPA axis and IRS dysregulations in schizophrenia could account, at least partly, for the better clinical stabilization achieved in patients treated with the latter drugs compared to those receiving conventional neuroleptics.