White matter (WM), constituting nearly half of the human brain's mass, is pivotal for the rapid transmission of neural signals across different brain regions, significantly influencing cognitive processes like learning, memory, and problem-solving. The integrity of WM is essential for brain function, and its damage, which can occur due to conditions such as multiple sclerosis (MS), stroke, and traumatic brain injury, results in severe neurological deficits and cognitive decline. The primary objective of this book chapter is to discuss the clinical significance of fluid biomarkers in assessing WM damage within the central nervous system (CNS). It explores the biological underpinnings and pathological changes in WM due to various neurological conditions and details how alterations can be detected and quantified through fluid biomarkers. By examining biomarkers like Myelin Basic Protein (MBP), Neurofilament light chain (NFL), and others, the chapter highlights their role in enhancing diagnostic precision, monitoring disease progression, and guiding therapeutic interventions, thus providing crucial insights into maintaining WM integrity and preventing cognitive and physical disabilities.