Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) is a form of periodic breathing, commonly observed in patients with heart failure (HF), in which central apneas alternate with hyperpneas that have a waxing-waning pattern of tidal volume. Uniform criteria by which to diagnose a clinically significant degree of CSR-CSA have yet to be established. CSR-CSA is caused by respiratory control system instability characterized by a tendency to hyperventilate. Central apnea occurs when Pa(CO(2)) falls below the threshold for apnea during sleep due to ventilatory overshoot. Patients with CSR-CSA are generally hypocapnic, with a Pa(CO(2)) closer than normal to the apneic threshold such that even slight augmentation in ventilation drives Pa(CO(2)) below threshold and triggers apnea. Factors contributing to hyperventilation in HF include stimulation of pulmonary irritant receptors by pulmonary congestion, increased chemoreceptor sensitivity, reduced cerebrovascular blood flow, and recurrent arousals from sleep. Controversy remains as to whether CSR-CSA is simply a reflection of HF severity, or whether it exerts unique adverse effects on prognosis. The main adverse influence of CSR-CSA on cardiovascular function appears to be excessive sympathetic nervous system activity due to apnea-related hypoxia and arousals from sleep. A number of studies have examined the potential relationship between CSR-CSA and mortality in HF. Most reported that CSR-CSA was associated with an increased risk for mortality, but these studies were small. Further research is therefore needed to elucidate mechanisms which contribute to the pathogenesis of CSR-CSA, and to determine whether its treatment can reduce morbidity and mortality in patients with HF.