The controversy around sirtuins and their functions in aging has drawn in the past few years as much attention, if not more, from the scientific community and the public as they did when first proposed as the key conserved aging regulators in eukaryotes. With some of the basic observations on sirtuin longevity promoting functions being questioned in popular model systems, researchers are wondering if this family of conserved enzymes still holds strong potential as therapeutic targets. This review examines the several controversial issues around sirtuins and their functions in aging, calorie restriction, as well as age-related diseases in light of recent studies in mammalian systems and discusses whether modulators of sirtuins still hold the secret of life.: