In the last few years, increasing effort has been devoted to better define the characteristics of tissue damage occurring outside MRI-visible lesions in patients with multiple sclerosis (MS) and, as a consequence, to improve our understanding of the disease pathobiology and of the mechanisms leading to the accumulation of irreversible disability. This book provides an updated review of the results obtained by leading research groups in this field. The potential clinical applications of what has been shown so far, as well as the areas for future research in the study of normal-appearing white and gray matter damage in MS are extensively discussed, making this book a valuable tool for clinical neurologists who are involved in the daily-life care of MS patients and for neuroscientists involved in MS research.