Intensive care unit-acquired weakness (ICUAW) begins within hours of mechanical ventilation and may not be completely reversible over time. It represents a major functional morbidity of critical illness and is an important patient-centered outcome with clear implications for quality of life and resumption of prior work and lifestyle. There is heterogeneity in functional outcome related to ICUAW across various patient populations after an episode of critical illness. This state-of-the art review argues that this observed heterogeneity may represent a clinical spectrum of disability in which there are recognizable clinical phenotypes for outcome according to age, burden of comorbid illness, and ICU length of stay. It further argues that these functional outcomes are modified by mood, cognition, and caregiver physical and mental health. This proposed construct of clinical phenotypes will be used as a framework for a review of the current literature on the molecular biology of muscle and nerve injury. This translational approach for the development of models pairing clinical phenotypes for different functional outcomes after critical illness with molecular mechanism of injury may offer unique insights into the diagnosis and treatment of muscle and nerve lesions.