Multiple sclerosis (MS) is thought to be an autoimmune disease with a chronic inflammatory response directed against central nervous system (CNS) myelin antigens. Immunologic studies indicate that autoreactive CD4+ lymphocytes migrate into the CNS causing blood brain barrier (BBB) disruption, an initial event in the evolution of the MS lesion. Subsequent antigen recognition within the CNS initiates inflammatory responses that, through the multiple effector mechanisms, lead to demyelination. Magnetic resonance imaging (MRI) studies provide new insights into the evolution of the MS lesion, revealing an active and continuous pathologic process that is not only localized to focal lesions, but also diffusely affects normal appearing white matter (NAWM). Standard T2-weighted images are exquisitely sensitive, showing changes due to inflammation, edema, demyelination, and axonal loss, but because of the lack of pathologic specificity, they only moderately correlate with the clinical parameters. New MRI techniques, including magnetic resonance spectroscopy, magnetization transfer, and diffusion imaging, provide a better measure of axonal loss and demyelination, the most clinically relevant components of MS lesions. Hopefully, they will enable us to more accurately monitor disease activity and evaluate the effects of new therapies on the progression of the disease.