Frailty has been identified as a promising condition for distinguishing different degrees of vulnerability among older persons. Several operational definitions have proposed fatigue as one of the features characterizing the frailty syndrome. However, such a subjective symptom is still not yet sufficiently explored and understood. Fatigue is a common and distressing self-reported symptom perceived by the person while performing usual mental and physical activities, highly prevalent in older people, and strongly associated with negative healthrelated events. The understanding of fatigue is hampered by several issues, including the difficulty at objectively operationalizing, the controversial estimates of its prevalence, and the complex pathophysiological mechanisms underlying its manifestation. Despite such barriers, the study of fatigue is important and might be encouraged. Fatigue may be the marker of the depletion of the body's homeostatic reserves to a threshold leading to its psycho-physical functional impairment, mirroring the concept of frailty. Its subjective and symptomatic nature resembles that of other conditions (e.g., pain, depression), which equally affect the individual's quality of life, expose to negative outcomes, and severely burden healthcare expenditures. In the present paper, we present an overview of the current knowledge on fatigue in older persons in order to increase awareness about its clinical and research relevance. Future research on this topic should be encouraged and developed because it could potentially lead to novel interventions against this symptom as well as against frailty and age-related conditions.