Trajectories of health and functioning with age show extreme variability among different individuals. Normal aging implies a progressive decline of physiological reserve and ability to compensate, but it is compatible with autonomy over the entire life span. In frail, older persons the decline in functional reserve is accelerated and compensatory mechanisms start failing, with high risk of homeostasis disruption and consequent negative health outcomes. Frailty is currently conceptualized as an age-related alteration in physiology and pathology that results into a typical constellation of signs and symptoms. Although current attempts to identify frail, older individuals for clinical purposes are based on measures of mobility and motor performance, candidate biological markers that may characterize the frailty syndrome start to emerge in the literature. These potential markers include, but are not limited to, soluble mediators of the inflammatory response, hormones, free radicals, antioxidants and macro- and micro-nutrients. This is a research area undergoing a rapid, dynamic development that may profit from new ways of defining disability outcomes in epidemiological studies of the elderly.