The primary biochemical theory of schizophrenia has centered on the role of dopaminergic dysfunction in the illness. The D2 receptor has been primarily indicated however, some atypical neuroleptics may not act at D2. The D4 receptor has a high affinity for the atypical antipsychotic clozapine and is therefore a potential target for drug design. The role of D4 in the aetiology of schizophrenia has, however, been the subject of controversy. Using radioligand binding assays some researchers have detected an elevation of D4-like receptors in schizophrenic striatum whilst conversely other workers claim that D4 receptors are undetectable in this region. Analysis of receptor levels is difficult due to the lack of a ligand selective for D4. We have therefore examined D4 at the level of gene expression. D4 mRNA levels have been examined in post-mortem frontal cortex from nine controls and eight schizophrenics using a reverse transcription-polymerase chain reaction (RT-PCR) method. No significant difference in D4 mRNA levels was found between the two groups. This result does not support a major role for variability of D4 gene expression in the aetiology of schizophrenia.