Making the diagnosis of multiple sclerosis (MS) remains a challenging problem for clinicians. The foundation of diagnosis rests on demonstrating neurologic lesions, predominantly in the white matter, that are disseminated over space and time. Diagnostic criteria guide the clinician through applying clinical, radiologic, and laboratory evidence to secure the diagnosis. Complicating the process, however, is the existence of other conditions that may resemble MS and mislead the clinician to the wrong diagnosis. A familiarity with the differential diagnoses of symptoms commonly associated with MS permits the clinician to make the most accurate diagnosis.