The pharmacotherapy of schizophrenia relies on restoring a dysregulated striatal dopamine and prefrontal cortex glutamate neurotransmission. However, these treatments are usually insufficient to fully cover all the disease symptomatology (i.e., negative and cognitive symptoms). Thus, the search for alternative and/or complementary neurotransmitter systems involved in the etiology of schizophrenia constitutes a big challenge in psychiatry these days. Adenosine, a well known neuromodulator in the central nervous system, has been highlighted because its relationship with both dopaminergic and glutamatergic neurotransmission. Indeed, the disruption of adenosine homeostasis in the adult brain has multiple consequences in the circuitry implicated in the pathophysiology of schizophrenia. Consequently, the "adenosine hypothesis of schizophrenia" foresees that the disruption of adenosine homeostasis within certain brain areas has behavioral consequences resembling schizophrenia symptoms. Thus, it has been postulated that restoring adenosine concentration within the schizophrenia-related brain areas might have beneficial antipsychotic properties. Overall, as adenosine dysfunction can trigger endophenotypes of schizophrenia, the development of drugs targeting the adenosinergic system will definitely constitute a new opportunity for therapeutic intervention in schizophrenia.