Frailty is the major contributor to health care problems and poor quality of life in older people. Although frailty is recognised to be multifactorial, the major contributor is thought to be skeletal muscle weakness. By the age of 70, the average human has lost approximately 30% of skeletal muscle and 40% of maximum force generation (1). This decline in neuromuscular function and strength and lack of functional reserve increases the risk of falls, hypothermia, incontinence and contributes to increasing lack of independence. The mechanism(s) by which the development of this age related loss of muscle mass and function occurs are poorly understood although a failure in the ability to activate the stress or Heat shock response has been implicated. The Heat shock protein (HSP) content of skeletal muscle of adult mammals is increased following both short and long-term exercise protocols. In contrast the HSP content and the ability to activate a stress response are modified in skeletal muscle with age (2). Transgenic studies have demonstrated that this blunted response plays a key role in development of age-related functional deficits. Lifelong overexpression of the cytosolic HSP, HSP70 in skeletal muscle of mice prevented the age-related loss of specific force (force/cross sectional area(CSA)) generation but not the age-related loss of maximum tetanic force generation observed in muscles of old wild type mice (3). In addition, and unlike muscles of old wild type mice, HSP70 overexpression facilitated the complete recovery of force generation in EDL muscles of old transgenic mice at 28 days following a severe protocol of damaging lengthening contractions. Further studies have demonstrated that lifelong overexpression of the mitochondrial chaperone, HSP10 in skeletal muscle of mice prevented the age-related loss of force and CSA observed in quiescent muscles of old wild type mice and furthermore, protected muscles of both adult and old mice from damage following contraction-induced injury. These data demonstrate that the development of all aspects of age-related muscle weakness and atrophy are not inevitable. The protective effect of overexpression of HSP10 in the mitochondria of skeletal muscle strengthens the hypothesis of the involvement of mitochondrial dysfunction in the development of these deficits and the differential effects of different HSPs highlight the specific functions of individual HSPs in skeletal muscle. The mechanism responsible for the inability to activate a stress response in old muscle is unclear although modified signalling by Reactive Oxygen Species is thought to play a role. Data suggest that the defect occurs prior to dissociation of the Heat Shock transcription factor, HSF1 from an inactive to an active form in the cytosol since data from mice treated with the HSP90 inhibitor and HSF1 activator, 17-AAG, demonstrate an increased HSP70 content of skeletal muscles of adult and old mice (4).