There are numerous reports of increased use of both caffeine and nicotine in schizophrenia. Clinical effects of these substances are important and may complicate the interpretation of schizophrenia symptoms and antipsychotic medication side effects. Use of caffeine and nicotine is often linked, with smokers using more caffeine due to interacting metabolic effects. Studies of neurobiology reveal evidence of specific brain changes in schizophrenia that are impacted by nicotine and caffeine and suggest self-medication effects. Interestingly both substances are linked to altered inhibitory mechanisms in brain functioning. Few studies have examined both simultaneously which is critical given their metabolic and symptomatic interactions. This paper reviews use of caffeine and nicotine in people with schizophrenia and gives recommendations for their further study.