Obstructive sleep apnea is a common disorder with many different comorbidities. Patients can present with these comorbidities even when sleep apnea has not been diagnosed due to the low diagnostic rates for obstructive sleep apnea worldwide. This presents a concern for clinicians as unless sleep apnea is treated along with a presenting comorbidity, the patient will not have an optimal health outcome. This chapter addresses several of the most common and worrisome comorbidities of sleep apnea and discusses the relationships and pathophysiology of comorbidities including insomnia, treatment resistant hypertension, restless legs syndrome, depression, gastroesophageal reflux, asthma, cognitive disorder, REM sleep behavioral disorder and paroxysmal atrial fibrillation. Clinical studies documenting the relationships of each of these comorbidities to obstructive sleep apnea are presented with putative pathophysiologic discussion of how obstructive sleep apnea aggravates or leads to the development of each of these illnesses.