Obesity has epidemic proportions in Western societies and, because of its significant association with morbidity and mortality, is a major public health issue. Excessive daytime sleepiness (EDS) and fatigue (tiredness without increased sleep propensity)--which have been associated with obesity--have a significant impact on individual well-being and public safety. In this article, we review data that challenge the belief that sleep apnea and sleep disruption per se are the primary determinants of obesity-related daytime sleepiness and fatigue. Specifically, it appears that obesity per se is associated with objective and subjective daytime sleepiness compared to normal-weight controls regardless of sleep apnea and sleep loss. Indeed, obese patients without sleep apnea are sleepier compared to nonobese controls whereas within the morbidly obese, those who have high sleep efficiency at night are sleepier than those who have low sleep efficiency. In addition, in recent studies based on large random samples of the general population, the primary determinants of subjective EDS were depression and metabolic disturbances, that is, obesity/diabetes, and not sleep apnea or objective sleep disruption. Furthermore, sleepiness and fatigue are very prevalent in conditions associated with insulin resistance, for instance, the polycystic ovary syndrome (PCOS), independently of sleep apnea or obesity, or in conditions of insufficient physical activity. On the basis of these data, we propose that obesity-related objective daytime sleepiness and fatigue are associated primarily with metabolic and psychological factors and less with sleep apnea and sleep disruption per se. Furthermore, we suggest that objective sleepiness is primarily related to metabolic factors, whereas fatigue appears to be related to psychological distress. Finally, based on data from studies in normal controls and patients with sleep disorders, we propose that the interaction of the hypothalamic-pituitary-adrenal (HPA) axis and proinflammatory cytokines determines the level of sleep/arousal within the 24-h cycle, that is, "hypercortisolemia" plus hypercytokinemia is associated with low sleep efficiency and fatigue, whereas "eucortisolemia" or "hypocortisolemia" plus hypercytokinemia is associated with high sleep efficiency and objective sleepiness.