It is estimated that there are 300,000 people with multiple sclerosis (MS) in the United States and 2.3 million worldwide. Each MS attack can affect function in cognitive, emotional, motoric, sensory, or visual domains. Patients are often struck in the prime of their lives as they attempt to move forward with career, and family. Since the previous 2010 Seminars in Neurology Pearls and Pitfalls issue, the world of MS has drastically changed and advanced. Here the authors address the ever-changing MS world in both treatment options and diagnostics, covering easily missed differential diagnoses, newly available immunomodulatory therapy, and the challenges of safely treating patients.