Human skeletal muscles are continually remodeled to match the function required of them. Diameter, strength, and vascular supply are altered when a muscle group experiences contraction and resistance. The purpose of this article is to describe selected muscle signaling pathways that contribute to muscle remodeling. Multiple factors affect the cellular and molecular remodeling of muscles and at least 2 of them—exercise and protein/calorie delivery—are under the direct care of intensive care unit (ICU) clinicians. Activating signaling pathways may promote preservation of muscle mass and function. Interventions to prevent muscle atrophy have potential to reduce ICU-acquired weakness and positively affect quality of life in survivors after ICU hospitalization. Exploring information generated by genomic and proteomic investigations about muscle signaling pathways can help the ICU clinician evaluate the benefits and risks of interventions to maintain muscle health early in critical illness.