Gadolinium (Gd)-enhanced MR imaging has greatly improved the understanding of the pathophysiology of multiple sclerosis (MS) and has provided robust outcome measures for monitoring MS activity. Modest correlation between the presence and extent of enhancement and the evolution of MS probably owes to the limited sensitivity and specificity of conventional Gd-enhanced MRI. Triple dose of Gd may enable better assessment of the presence and extent of "low-grade" MS inflammation. Cell-specific imaging techniques and multiparametric MR imaging studies should increase understanding of the pathologic steps between inflammation and irreversible tissue loss, and consequently, better define the mechanisms leading to irreversible neurological disability in MS. Clinical applications of Gd-enhanced MR imaging should include the diagnostic work-up of MS patients, and the assessment of their disease activity over time, in the context of natural history studies or clinical trials. Gd-enhanced MR imaging should always be obtained at presentation in patients with clinically isolated neurological syndromes, because of its ability to show the time dissemination of lesions, and its high predictive value for subsequent evolution to clinically definite MS. In patients with established MS, however, the usefulness of Gd-enhanced MR imaging should depend strictly on specific clinical settings or research questions.