The complex, highly integrative endocrine system regulates all aspects of somatic maintenance and reproduction and has been widely implicated as an important determinant of longevity in short-lived traditional model organisms of aging research. Genetic or experimental manipulation of hormone profiles in mice has been proven to definitively alter longevity. These hormonally induced lifespan extension mechanisms may not necessarily be relevant to humans and other long-lived organisms that naturally show successful slow aging. Long-lived species may have evolved novel anti-aging defenses germane to naturally retarding the aging process. Here, we examine the available endocrine data associated with the vitamin D, insulin, glucocorticoid and thyroid endocrine systems of naturally long-living small mammals. Generally, long-living rodents and bats maintain tightly regulated lower basal levels of these key pleiotropic hormones than shorter lived rodents. Similarities with genetically manipulated long-lived rodent models of aging suggest that evolutionary well-conserved hormonal mechanisms are integrally involved in lifespan determination.