ICU-acquired weakness is defined as bilateral symmetrical limb weakness and occurs in 50% of patients requiring mechanical ventilation for >=7 days, with studies confirming that the presence and severity of weakness are independent risk factors for death. There has been a focus on the identification and pathophysiology of muscle weakness and wasting in critically ill patients. However, due to technical restrictions of using neurophysiological and non-volitional strength measurements and the limited correlation between strength and these neurophysiological measurements, attention has more recently focussed on measurements of muscle wasting. This is a rationale approach as a linear relationship has been shown to be present between quadriceps muscle strength and rectus femoris cross- sectional area. Immobilisation, as occurs in all patients with critical illness, has been shown to modify skeletal muscle morphology, the proportion of slow and fast muscle fibres, contractility, aerobic capacity, muscle protein synthesis and subsequent physical activity. Although there are data reporting the loss in muscle mass with immobilisation, reduced muscle protein synthesis (MPS) response to excess dietary amino acid loading and insulin inhibition of muscle protein breakdown (MPB) without an effect on MPS, these data are from animal models and healthy subjects and currently there is little data in critically ill patients. Progress in the understanding of the muscle signalling pathways which mediate skeletal muscle hypertrophy and atrophy allows hypotheses to be generated to facilitate drug design and discovery. A rational approach would be to develop drugs that inhibit MPB pathways during skeletal muscle atrophy or stimulate MPS pathways during hypertrophy to develop anti- atrophy or pro-hypertrophy drugs. In addition to drug development, data on muscle signalling pathways and protein turnover will allow us to optimise the timing for muscle training both during and after critical illness.