A major contributor to frailty is skeletal muscle weakness. The decline in neuromuscular function and strength and lack of functional reserve with age 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 an altered generation of reactive oxygen species (ROS) and a failure in the ability to adapt to stress by activation of the stress or heat shock response have been implicated. ROS generation is increased in skeletal muscles of adult mice following a period of isometric contractions and this is associated with increased Heat Shock Protein (HSP) content of the muscle (1). In contrast ROS activities and the ability to activate a stress response are modified in skeletal muscle with age (1, 2). Transgenic studies have demonstrated that this blunted stress 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 generation but not the age-related loss of maximum tetanic force generation observed in muscles of old wild type (WT) mice (3). Unlike muscles of old WT 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. This effect was mimicked in muscles of old WT mice treated with a pharmacological inducer of HSP70 (4). The mechanisms by which lifelong or an acute increase in muscle content of HSP70 provide this protection are unclear although data demonstrate that lifelong overexpression of HSP70 results in a reduction in the accumulation of markers of oxidative stress in old mice and reverses this inability to activate NFkB following contractile activity (5). 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 decrease in cross-sectional area observed in quiescent muscles of old WT mice and protected muscles of both adult and old mice from damage following contraction-induced injury. Data demonstrate that mice lacking Cu,Zn superoxide dismutase (Sod1-/- mice) showed an accelerated loss of skeletal muscle mass and function (6) and studies of the adaptive responses in muscles of adult Sod1-/- mice show aberrant DNA binding activity of AP-1 and NF-kB which is similar to that observed in muscles of old WT mice (1). These data demonstrate that the development 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 an 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 ROS is thought to play a role. Data suggest that the defect in activation of HSP transcription occurs prior to dissociation of the Heat Shock transcription factor, HSF1 from an inactive to an active form in the cytosol since mice treated with the HSP90 inhibitor and HSF1 activator, 17-AAG, demonstrate an increased HSP70 content in skeletal muscles of both adult and old mice (4).