Over the last three to four decades, it has been observed that the average total hours of sleep have decreased to less than seven hours per person per night. Concomitantly, global figures relating to obesity and diabetes mellitus have increased in an alarming fashion in adults and children, and it has been hypothesized that neuro-hormonal changes accompanying this behavioral sleep deprivation may lead to insulin resistance and, subsequently, to diabetes mellitus. Sleep deprivation has been associated with multiple physiological changes, including increased cortisol and ghrelin levels, decreased leptin levels and impaired glucose metabolism. Experimental studies have also shown an increase in inflammatory and pro-inflammatory markers, which are indicators of body stress, under sleep deprivation. This review elaborates further on this hypothesis, exploring the molecular basis for the link between both entities and the underlying pathophysiology that results in insulin resistance and diabetes mellitus. We review the results of experimental and epidemiological studies, specifically examining the relationship between sleep duration and the immune and endocrine systems.