Calorie restriction (CR) is the most potent regimen known to extend the life span in multiple species. CR has also been shown to ameliorate several age-associated disorders in mammals and perhaps humans. CR induces diverse metabolic changes in organisms, and it is currently unclear whether and how these metabolic changes lead to life span extension. Recent studies in model systems have provided insight into the molecular mechanisms by which CR extends life span. In this review, we summarize and provide recent updates on multiple nutrient signaling pathways that have been connected to CR and longevity regulation. The roles of highly conserved longevity regulators--the Sirtuin family--in CR are also discussed.