Obesity-hypoventilation syndrome (OHS), also historically described as the Pickwickian syndrome, consists of the triad of obesity, sleep disordered breathing, and chronic hypercapnia during wakefulness in the absence of other known causes of hypercapnia. Its exact prevalence is unknown, but it has been estimated that 10% to 20% of obese patients with obstructive sleep apnea have hypercapnia. OHS often remains undiagnosed until late in the course of the disease. Early recognition is important because these patients have significant morbidity and mortality. Effective treatment can lead to significant improvement in patient outcomes, underscoring the importance of early diagnosis. The authors review the definition and epidemiology of OHS, in addition to the current multifaceted understanding of the pathophysiology, and provide useful clinical approaches to diagnosis and treatment.