Calorie restriction (CR) is one of the most powerful ways to extend life span. This chapter describes the history of the CR concept development, the impact of CR on the organ systems most vulnerable to senescence, intracellular consequences of CR and intracellular targets of CR mimetics. The recent findings on molecular mechanisms underlying effects of the most prominent mimetics of CR, namely metformin, resveratrol and rapamycin, are discussed. Particular emphasis is put on activation of autophagy by CR and its mimetics, as well as the role of the Nrf2/Keap1 pathway for longevity.