A sedentary lifestyle is one of the risk factors for a wide range of neurological and psychiatric diseases. Molecular and biochemical evidences support that sedentary lifestyle, excessive calorie intake and obesity can lead to a progressive decline in cognitive function. Studies on rodent models suggest that aerobic training can enhance cognitive skills irrespective of age. It improves blood flow in the brain, encourages the formation of new neurons and increases the number of synaptic connections between the neurons. Exercise prevents memory loss by reducing feelings of stress, anxiety and depression. Most of the results interlinking physical inactivity to loss in cognition are from studies on cerebral cortex and hippocampus, regions that are known for learning and memory. Further, exercise when initiated in the sedentary may result in adaptive cellular responses and up-regulation of genes responsible for neurogenesis in these regions. A few examples have been discussed on the brain from sedentary animals and humans, and the influence of exercise in protecting from accelerated loss in cognitive function in the physically inactive subjects. © 2011 Nova Science Publishers, Inc. All rights reserved.