Differentiating multiple sclerosis (MS) from alternative demyelinating diseases of the central nervous system and systemic medical conditions that mimic MS is challenging. A simple three-step approach is used in this text to guide readers through clinical cases to define MS and rule out competing causes. Case presentations are used to illustrate simple pearls and other clues that will aid clinicians in assessing and managing difficult clinical situations. The chapters are organized to reflect challenges regarding specific anatomical territories affected by MS and its mimickers, namely evaluation of impairment in the optic nerves, brain, brainstem, cerebellum, and spinal cord. Specific examples are used where the author or the treating physician was correct or incorrect in investigating or managing a particular question. The wisdom of hindsight thus generated becomes an invaluable and enduring lesson. The text is written in a coaching style, buttressed by the strong pedagogic wisdom of the author.