Skeletal muscle wasting and weakness are common complications associated with admission to the intensive care unit (ICU), with the loss of muscle mass and function increasing mortality and contributing to physical impairments post-discharge. While our understanding of the pathophysiology of this condition, commonly termed 'ICU-acquired weakness' (ICU-AW), has advanced considerably, no effective therapies are available. ICU-AW broadly encompasses a range of muscle-related impairments in this setting, including, but not limited to, critical illness myopathy and sepsis-induced myopathy. Pre-clinical models of critical illness can provide insights into the mechanisms underlying muscle wasting and weakness. Cell culture systems can provide mechanistic interrogation, by isolating effects to skeletal muscle directly. Small animal models, like rats and mice, allow for mechanistic investigation of ICU-AW using genetic models and testing pharmacological interventions. Larger animal models, including pigs and sheep, facilitate repeated blood and tissue sampling and can more closely recapitulate the standard-of-care within ICU settings. Although animal models can be advantageous for scientific investigation, they also have important limitations. Barriers to developing effective interventions include difficulty in obtaining muscle biopsies from patients, translating experimental findings between animal models and humans and replicating aspects of different ICU settings. This review explores the advantages and shortcomings of different pre-clinical models of critical illness, identifies gaps in understanding muscle wasting and weakness in critical illness and provides recommendations for improving the translation of therapeutics to promote functional recovery for patients post-discharge.