Frailty is a potentially reversible state of increased vulnerability to negative health-related outcomes that occurs as a result of multisystem biological impairment and environmental aspects. Given the relevance of this condition in both clinics and research, biomarkers of frailty have been actively sought after. Although several candidate biomarkers of frailty have been identified, none of them has yet been incorporated in the assessment or monitoring of the condition. Over the last years, increasing research interest has been focused on myokines, a set of cytokines, small proteins and proteoglycan peptides that are synthetized, expressed and released by skeletal myocytes in response to muscular contractions. Myokines may act in autocrine, paracrine, and endocrine manner and regulate several processes associated with physical frailty, including muscle wasting, dynapenia, and slowness. This review discusses the rationale to support the use of myokines as biomarkers of frailty in older adults.