Cellular stress resistance has been observed in a variety of long-lived mouse systems. The Ames and Snell dwarf mice show altered hormonal profiles (low levels of growth hormone/IGF-1 and of other hormones). These altered hormonal profiles lead to physiological changes in cells, leading to increased resistance to multiple forms of stress including UV light, oxidative stress, heat, and the heavy metal cadmium. The cells also show resistance to carcinogen and senescence-like growth arrest induced by ambient oxygen. Thus, cellular stress resistance may confer resistance to various diseases associated with stress insults. Stress resistance has also been observed in various long-lived mice (hemizygous knockout of igf-1r, a mutation in p66(shc), and klotho overexpression) and in vitro CR (Carolie Restriction) system. Many of the long-lived mouse systems show reduction or inhibition of the insulin/IGF-1-FOXO pathway, thus suggesting that there may be an overlapping mechanism for increased life span. The insulin/IGF-1-FOXO pathway interlocks to several signal transduction pathways through AKT, FOXO, JNK, and other components. Taken together, stress resistance may be an essential function in cells that leads to increased longevity. I will summarize molecular basis of stress resistance and further discuss stress resistance in other systems.