The rate of comorbid depression and medical illness varies from 10 to 40%. Over the years, there has been a paucity of studies completed despite the importance of knowing which antidepressants are the most effective and safest to use in comorbid states. In this review, focus is placed on disorders in these important areas: cardiovascular disease, neurological disorders, diabetes mellitus and cancer. Cardiovascular disease complications can be related in many cases to platelet clumping produced by medications; reductions in morbidity can be achieved by reducing platelet adhesiveness. Specific results have shown sertraline administration to be safe in the post myocardial infarction (MI) state. This is a time of depression-induced increases of 200-300% in mortality. Evidence for safe administration of bupropion, as well as the selective serotonin re-uptake inhibitors (SSRIs) fluoxetine and paroxetine, is also available. The appearance of major depression and diabetes mellitus has been successfully treated with fluoxetine, sertraline and nortriptyline (NTI), however, NTI may lead to a worsening of glucose indices due to its noradrenergic specificity. Regarding neurologic disorders, there is controlled data showing the safety and efficacy of citalopram, sertraline and fluoxetine in post stroke depression. Parkinson's disease has been associated frequently with depression, as might be expected from its characteristic dopamine deficient state. For perhaps the same reason, the agents that can block re-uptake of dopamine i.e., tricyclic antidepressants (TCAs), have been effective in comorborbid depression with Parkinson's disease. In dementia, there is a paucity of information on new agents. However, double-blind data seems to show efficacy for sertraline, paroxetine and citalopram. There are few studies of cancer-related depression treated in a controlled fashion with antidepressants; imipramine, amitriptyline, fluoxetine, paroxetine, mirtazapine and mianserin (not available in the USA) all have support from some published studies.