Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS). Traditionally, MLD has been classified according to age at onset (late-infantile, early-juvenile and late-juvenile, and adult MLD), with earlier forms leading to more rapid neurologic decline. New data show that the type of presenting symptoms further influences the dynamic of disease progression. Patients with a cognitive presentation have a much slower or even no motor decline than patients with a mixed motor and cognitive presentation. Research advancements have enabled improved understanding of the effects of allogeneic hematopoietic stem cell transplantation and the development of novel therapeutic approaches, including hematopoietic stem cell gene therapy, which is now authorized in the EU, United Kingdom, and United States as treatment for selected patients with early-onset forms of MLD. Both hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are most effective when administered before disease onset. To identify presymptomatic patients, NBS for MLD is becoming available in several countries, resulting in new challenges. Decisions regarding patient eligibility for these treatments in already symptomatic individuals, as well as the timing of treatment for patients identified through NBS, require thorough understanding of disease progression. Biomarkers may be helpful for disease staging and prediction of disease evolution. Moreover, apart from timing, challenges remain regarding optimal treatment strategies across MLD subtypes, especially late-onset MLD, and management of the clinical heterogeneity and course of the disease. Another important issue is ensuring therapy accessibility, which forms a substantial barrier for equitable care. Continued research and international collaboration are essential to address these challenges, with the goal of improving care and outcomes for patients with MLD and their families.