With the percentage of the population above age 65 expected to double by 2030, the healthcare costs across neurodegenerative diseases will in all likelihood significantly increase. As such, disease-modifying, preventive strategies are urgently needed. However, despite major technological advances and massive concerted efforts, we still fall short of disease prevention, delayed progression or reversal when it comes to neurodegenerative diseases. An increasing wealth of information has come to formally demonstrate that exercise serves as one of the best strategies for coping with neurodegeneration. Herein, we review the available evidence on how and to which extent physical activity can expand one's motor reserve in the settings of neuropathology and ageing. Individuals who attain higher levels of functionality via lifelong experience develop a higher motor reserve throughout life and clinically relevant symptoms only later in life. The higher the motor reserve, the higher the degree of resilience and the better individuals can cope with a given level of neuropathology. Physical exercise is an efficacious and efficient way of strengthening one's motor reserve, allowing for an increased ability to cope with neuropathology throughout life and resulting in delayed disease onset and progression. Motor learning, and not necessarily motor performance, seems to be the key when aiming at maximizing the benefits of physical exercise in the context of motor reserve. As a result, a variety of challenging activities are to be recommended and maintained throughout life.