Complex sleep apnea syndrome (CompSAS) describes the coexistence or appearance and persistence of central apneas or hypopneas in patients with obstructive sleep apnea upon successful restoration of airway patency. We review data on treatment of CompSAS with CPAP, bilevel positive airway pressure, and adaptive servoventilation and discuss evidence for the addition of medications (analgesics, hypnotics, acetazolamide) and gases (oxygen, CO2) to positive airway pressure therapy. Future research should focus on defining outcomes in patients with CompSAS and allow for more accurate tailoring of therapy to the pathophysiology present in the individual patient.