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Societies are progressively aging, with the oldest old (i.e., those aged >80-85 years) being the most rapidly expanding population segment. However, advanced aging comes at a price, as it is associated with an increased incidence of the so-called age-related conditions, including a greater risk for loss of functional independence. How to combat sarcopenia, frailty, and overall intrinsic capacity decline in the elderly is a major challenge for modern medicine, and exercise appears to be a potential solution. In this article, we first summarize the physiological mechanisms underlying the age-related deterioration in intrinsic capacity, particularly regarding those phenotypes related to functional decline. The main methods available for the physical assessment of the oldest old are then described, and finally the multisystem benefits that exercise (or "exercise mimetics" in those situations in which volitional exercise is not feasible) can provide to this population segment are reviewed. In summary, lifetime physical exercise can help to attenuate the loss of many of the properties affected by aging, especially when the latter is accompanied by an inactive lifestyle and benefits can also be obtained in frail individuals who start exercising at an advanced age. Multicomponent programs combining mainly aerobic and resistance training should be included in the oldest old, particularly during disuse situations such as hospitalization. However, evidence is still needed to support the effectiveness of passive physical strategies including neuromuscular electrical stimulation or vibration for the prevention of disuse-induced negative adaptations in those oldest old people who are unable to do physical exercise. © 2019 American Physiological Society. Compr Physiol 9:1281-1304, 2019., (Copyright © 2019 American Physiological Society. All rights reserved.)