This paper reviewed and discussed co-occurring medical and substance use disorders in persons with bipolar disorders and the effect of comorbidity in terms of hospitalization, outcomes of treatment, life time expectancy, independent living, and quality of life. Bipolar disorder is common, disabling and severe and persistent mental illness. It is one of the most severe disabling, heterogeneous and economically catastrophic medical disorders. The complexity of bipolar disorder is often caused by the presence of comorbid conditions. Medical and substance use comorbidities are common among patients with bipolar disorder, with an estimated prevalence of 60% and associated with complicated treatment increased time of hospital stay and increase risk of death. The life time expectancy of persons with bipolar disorder is shorter than general populations. Persons with bipolar disorder die roughly 7 years earlier than those without the disorder. Alcohol use disorders are particularly common among persons with bipolar disorder, with a lifetime prevalence of roughly 50%. It is estimated that comorbid medical disorders occurs in 67% of persons with Bipolar disorder, of which most of them remain undetected.