Sleep loss has been a common practice in modern society. However, it has been only recently that the effects of sleep loss on human health have received more attention. This review summarizes the experimental findings of the effects of total and partial sleep deprivation on stress hormones and pro-inflammatory cytokines. Specifically, studies have consistently demonstrated that total or partial sleep loss is associated with increased sleepiness and decreased performance and elevation of pro-inflammatory cytokines, i. e., IL-6 and TNF-alpha, which have been proposed as mediators of excessive daytime sleepiness and cardiometabolic morbidity in humans. In addition, non-stressful sleep loss is not associated with elevation of cortisol, the end-product of the hypothalamic-pituitary-adrenal (HPA) axis. Also, alertness and performance measured with objective tests (Multiple Sleep Latency Test and Performance Vigilance Test) are significantly impaired following total or partial sleep loss. Furthermore, napping or extended sleep have been shown to decrease sleepiness, improve performance and cause beneficial changes in cortisol and IL-6 secretion. Collectively, these studies show that sleep loss has adverse effects on alertness, performance and inflammation markers suggesting that insufficient sleep may influence health and longevity in a negative manner. On the other hand it appears that more sleep either in the form of napping or extended sleep may protect from these adverse effects of sleep loss.