Over the past several years, the image of MS has been changing from distinct categories of disease to a complicated spectrum of interwoven pathologies. As this knowledge evolves, so do approaches to prognosticating, monitoring, and responding to disease. With many markers of progression still under investigation and therefore not included in modern guidelines, MS clinicians are left on their own to decide which factors should hold the most weight in influencing clinical decisions. In this “debate-themed” symposium originally held in conjunction with the 2023 ACTRIMS Forum, Drs Shin, Alvarez, and Oh advocate for their preferred disease indicators and why they are the future of successful MS disease management. In the absence of professional guidelines, these expert perspectives may deepen the understanding of exactly how and why these factors should be considered, improving clinicians’ ability to navigate and optimize available tools and strategies for their own patients.