Frailty is a syndrome characterized by decreased reserves across multiple physiologic systems resulting in functional limitations and vulnerability to new stressors. Physical frailty develops over years in community-dwelling older adults but presents or worsens within days in the intensive care unit (ICU) because common mechanisms governing age-related physical frailty are often exacerbated by critical illness. The hallmark of physical frailty is a combined loss of muscle mass, force, and endurance. About one-third of ICU patients have frailty before hospitalization, which increases their risk for both short- and long-term disability and mortality. While there are several valid ways to measure clinical frailty in patients before or after an ICU admission, the mechanistic underpinnings of frailty in critically ill patients and ICU survivors have not been thoroughly investigated. Furthermore, therapeutic interventions to treat frailty during and after time in the ICU are lacking. In this narrative review, we examine studies that identify potential biological mechanisms underlying the development and propagation of physical frailty in both aging and critical illness (eg, inflammation, mitochondrial myopathy, and neuroendocrinopathy). We discuss specific aspects of these frailty mechanisms in older adults, critically ill patients, and ICU survivors that may represent therapeutic targets. Consistent with complexity underlying frailty, this syndrome is unlikely to result from an excess of a single harmful mediator or deficit of a single protective mediator. Rather, frailty occurs in the presence of an incompletely understood state of multisystem dysregulation. We further describe knowledge gaps that warrant clinical and translational research in frailty and critical care with an overall goal of developing effective frailty treatments in critically ill patients and ICU survivors.