Multiple sclerosis (MS) affects 400,000 Americans and is the leading nontraumatic cause of neurological disability in young adults. Although MS is progressive, it is not fatal, and patients generally have a normal lifespan. However, progressive disability imposes increasing limitations and reduced quality of life for these patients. Newly released consensus guidelines offer neurologists and primary care physicians direction to improve the differential diagnosis and develop strategies to facilitate early and accurate diagnosis of MS. A number of factors must be considered when selecting a treatment regimen for patients with MS, including variations in clinical and MRI evidence of disease. The discovery and broad application of MRI in medicine has led to an increased awareness of the number of patients with incidental white matter pathology in the CNS. The natural history or evolution of such individuals with respect to their risk of developing MS is unclear, but a need for further studies on this subject and physician awareness is essential for progression of disease therapy in MS. In this two-part neuroscienceCME Journal Club series, the authors will translate their research and provide insights and application to clinical practice. Featured Article: Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008;14:1157-1174.