Psychotropic substance abuse and addiction are very prevalent among individuals with major psychiatric disorders world wide. However, this significant association is poorly explained. The dopaminergic circuits have been implemented in addiction as well as in schizophrenia. Recently the important role of glutamatergic neurotransmission has gained attention and current theoretical models of psychosis and substance abuse support the role of interactions between glutamate and other neurotransmitters in the patho-physiology of both disorders. However, the identification of the underlying genetic risk factors remains challenging and not a single genomic variant has been identified with certainty, possibly due to important limitations of the methods used. Clinical trials with glutamatergic neurotransmission modulators, even though still controversial, support the role of glutamate in psychosis and justify further research.