In this review we will describe the cognitive deficiency in Multiple Sclerosis (MS) and analyze the relationship between the performance on neuropsychological tests and the anatomofunctional findings assessed by neuroimaging techniques. Memory, abstract reasoning, and visuospatial abilities impairments are correlated with lesion extension and with corpus callosum atrophy, quantified on MRI. On the other hand, in MS patients with cognitive disturbance, PET and SPET studies show metabolic alterations and perfusion deficits at the cortical level, particularly in the left hemisphere and in the frontal and temporal lobes.