Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS), affecting over 2 million people globally, with ~400,000 in the United States. It is characterized by episodes of neurological disability that can be reversible, followed by a progressive course in many patients, leading to impaired mobility and cognition. Over a dozen disease-modifying medications are available to reduce relapses and limit white matter lesions on MRI, but none fully prevent or reverse progressive disability. The annual economic cost in the U.S. is approximately $10 billion. MS pathology involves disseminated demyelination, inflammation, and glial reaction, with lesions appearing throughout the CNS. Early active white matter lesions are heterogeneous and evolve over months. Lesion patterns suggest a single immune mechanism per individual, with evidence of immunoglobulin and complement in active lesions. Non-invasive biomarkers could help personalize treatment, as current therapies may not address the disease's heterogeneity. Lesions can occur in white and gray matter, with gray matter lesions being less inflammatory and having lower blood-brain barrier permeability. Subpial cortical lesions are often inflammatory and associated with leptomeningeal inflammation. Spinal cord lesions are a major source of disability, with demyelination often involving gray matter. MRI is critical for diagnosing and monitoring MS, with new lesions more frequent than clinical relapses. MRI findings are also useful in predicting disability progression. Biomarkers like MRI are essential for diagnosing and monitoring MS, but developing biomarkers for progressive MS is challenging due to the disease's slow progression and heterogeneous pathogenesis. MRI is the only technique that can assess the entire CNS in vivo, and recent advances in 7-tesla MRI and optical coherence tomography allow for detailed imaging of retinal changes, which correlate with brain MRI findings. Blood and cerebrospinal fluid (CSF) biomarkers, such as oligoclonal bands, are used in diagnosis, but their specificity is limited. CSF and serum neurofilament light chains show promise in reflecting axonal pathology. Therapies for MS include interferons, glatiramer acetate, monoclonal antibodies, and other drugs that reduce relapses and disability progression. Recent approvals include ocrelizumab for primary progressive MS, though its mechanism of action remains unclear. Research into MS pathogenesis highlights the role of adaptive and innate immune systems, with T and B cells, macrophages, and microglia playing key roles. Glial cells, including astrocytes and oligodendrocytes, are involved in both inflammation and repair. Axonal damage is common, with demyelination leading to axonal loss and neurodegeneration. Therapies aimed at remyelination and axonal protection are under investigation, with some showing promise in preclinical studies. Future directions include understanding the mechanisms of disease progression, developing targeted therapiesMultiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS), affecting over 2 million people globally, with ~400,000 in the United States. It is characterized by episodes of neurological disability that can be reversible, followed by a progressive course in many patients, leading to impaired mobility and cognition. Over a dozen disease-modifying medications are available to reduce relapses and limit white matter lesions on MRI, but none fully prevent or reverse progressive disability. The annual economic cost in the U.S. is approximately $10 billion. MS pathology involves disseminated demyelination, inflammation, and glial reaction, with lesions appearing throughout the CNS. Early active white matter lesions are heterogeneous and evolve over months. Lesion patterns suggest a single immune mechanism per individual, with evidence of immunoglobulin and complement in active lesions. Non-invasive biomarkers could help personalize treatment, as current therapies may not address the disease's heterogeneity. Lesions can occur in white and gray matter, with gray matter lesions being less inflammatory and having lower blood-brain barrier permeability. Subpial cortical lesions are often inflammatory and associated with leptomeningeal inflammation. Spinal cord lesions are a major source of disability, with demyelination often involving gray matter. MRI is critical for diagnosing and monitoring MS, with new lesions more frequent than clinical relapses. MRI findings are also useful in predicting disability progression. Biomarkers like MRI are essential for diagnosing and monitoring MS, but developing biomarkers for progressive MS is challenging due to the disease's slow progression and heterogeneous pathogenesis. MRI is the only technique that can assess the entire CNS in vivo, and recent advances in 7-tesla MRI and optical coherence tomography allow for detailed imaging of retinal changes, which correlate with brain MRI findings. Blood and cerebrospinal fluid (CSF) biomarkers, such as oligoclonal bands, are used in diagnosis, but their specificity is limited. CSF and serum neurofilament light chains show promise in reflecting axonal pathology. Therapies for MS include interferons, glatiramer acetate, monoclonal antibodies, and other drugs that reduce relapses and disability progression. Recent approvals include ocrelizumab for primary progressive MS, though its mechanism of action remains unclear. Research into MS pathogenesis highlights the role of adaptive and innate immune systems, with T and B cells, macrophages, and microglia playing key roles. Glial cells, including astrocytes and oligodendrocytes, are involved in both inflammation and repair. Axonal damage is common, with demyelination leading to axonal loss and neurodegeneration. Therapies aimed at remyelination and axonal protection are under investigation, with some showing promise in preclinical studies. Future directions include understanding the mechanisms of disease progression, developing targeted therapies