Frailty is a wasting syndrome of advanced age that leaves a person vulnerable to falls, functional decline, morbidity, and mortality. The cause of this syndrome is complex but likely has a biologic basis. Studies by the authors' research group have validated a phenotype of frailty [table: see text] and have established a gender difference in prevalence with women twice as likely to develop the syndrome as men. Using a biologic model that includes sarcopenia, neuroendocrine decline, and immune dysfunction as potential causes, several physiologic gender differences may explain these differing levels of frailty. First, higher baseline levels of muscle mass may protect men from reaching a threshold of weakness and muscle mass loss that may put them into a category of frailty. Specific neuroendocrine and hormonal factors that may make men less likely to develop frailty than women include testosterone and GH, which may provide advantages in muscle mass maintenance, and cortisol, which is likely less dysregulated in older men as compared to older women. There is also evidence of immune system dimorphism that is, in part, responsive to sex steroids, perhaps making men more vulnerable to sepsis and infection and women more vulnerable to chronic inflammatory conditions and muscle mass loss. The net effect of the hormonal dysregulation and immune system dysfunction is an accelerated loss of muscle mass. There is also evidence that lower levels of activity and lower caloric intake in women as compared to men may also influence the phenotype of frailty and make women more vulnerable then men to the syndrome.