MRI is the most important paraclinical measure for assessing and monitoring the pathologic changes implicated in the onset and progression of multiple sclerosis (MS). Conventional MRI sequences, such as T1-weighted gadolinium-enhanced and spin-echo T2-weighted imaging, are unable to provide full details about the degree of inflammation and underlying neurodegenerative changes. Newer nonconventional MRI techniques have the potential to detect clinical impairment, disease progression, accumulation of disability, and the neuroprotective effects of treatment. Unenhanced T1-weighted imaging can reveal hypointense black holes, a measure of chronic neurodegeneration. Two- and three-dimensional fluid-attenuated inversion recovery sequences allow better identification of cortical lesions. Ultrahigh-field strength MRI has the potential to detect subpial cortical and deep gray matter lesions. Magnetization transfer imaging is increasingly used to characterize the evolution of MS lesions and normal-appearing brain tissue. Evidence suggests that the dynamics of magnetization transfer changes correlate with the extent of demyelination and remyelination. Magnetic resonance spectroscopy, which provides details on tissue biochemistry, metabolism, and function, also has the capacity to reveal neuroprotective mechanisms. By measuring the motion of water, diffusion imaging can provide information about the orientation, size, and geometry of tissue damage in white and gray matter. Functional MRI may help clarify the brain's plasticity-dependent compensatory mechanisms in patients with MS. High-resolution microautoradiography and new contrast agents are proving to be sensitive means for characterizing molecular markers of disease activity, such as activated microglia and macrophages. Optical coherence tomography, a new research technique, makes it possible to investigate relevant physiologic systems that provide accurate measures of tissue changes secondary to the MS disease process. Although detecting the status of neuronal integrity using MRI techniques continues to improve, a "gold standard" model remains to be established.