This review focuses on research involving calorie restriction (CR) in humans and the resulting changes observed in endocrine and neuroendocrine systems. Special emphasis is given to the clinical science studies designed to investigate the effects of controlled, high-quality, energy-restricted diets on both biomarkers of longevity and on the development of chronic diseases of human aging. Prolonged CR has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats and mice. The biological mechanisms of this lifespan extension via CR are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity and functional changes in both neuroendocrine and autonomic nervous systems. Most of the difficulty in characterizing the systemic endocrine and neuroendocrine changes with aging and CR is due to the limited capability to collect large and multiple blood samples from small animals, which are usually shorter lived, and hence the most studied. Ongoing studies of prolonged CR in humans are now making it possible to analyze changes in the "biomarkers of aging" to unravel some of the mechanisms of its anti-aging phenomenon. With the incremental expansion of research endeavors in the area of energy restriction, data on the effects of CR in non-human primates and human subjects are becoming more accessible. Detailed analyses from controlled human trials involving long-term CR will allow investigators to link observed alterations from body composition and endocrine systems down to changes in molecular pathways and gene expression, with their possible effects on aging.