Comorbid depressive and anxiety disorders are associated with chronic physical illnesses. Treatment with antidepressants and mood stabilizers require knowledge about toxicity, potential side effects, and drug interactions. According to controlled studies in comorbid cardiovascular diseases, diabetes mellitus, and cerebrovascular disorders (post-stroke depression), serotonin-selective reuptake inhibitors (SSRIs), e.g., sertraline and citalopram, are preferred. Pramipexole, reboxetine, mirtazapine, or nortriptyline showed efficacy in treatment of Parkinson depression. Chronic pain syndromes can be improved with low-dose tricyclic antidepressants. Both establishment of compliance and follow-up examinations are essential. Combined treatment with psychotherapeutic interventions, including coping strategies, should be used whenever possible.