Especially when chronic, the presence of a somatic disorder is accompanied by various levels of psychological stress, which can range up to comorbidity with mental disorders. In addition, chronic somatic diseases and mental disorders are often interdependent. Treatment for persons with mental and somatic comorbidity is frequently offered in the context of medical rehabilitation. As skills of psychotherapists are concerned, comorbidity needs a bio-psychosocial approach in which knowledge of medicine, psychology, and social sciences is integrated. In addition to the expert skills of psychotherapists, interprofessional training, basic knowledge, and communication with physicians are necessary. The present article outlines conditions for outpatient psychotherapeutic care of persons with chronic somatic diseases and addresses central problems in the differential diagnosis of mental and somatic disorders as well as treatment indications when comorbidity is present. Selected examples for the diagnosis and treatment of patients with cardiovascular disorder and diabetes, respectively, illustrate these aspects.