<p>Atypical parkinsonian syndromes, such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), are neurodegenerative disorders characterized by rapid progression, limited treatment options, and clinical overlap, as well as frequent misdiagnosis with Parkinson’s disease (PD). Early and accurate diagnosis, together with reliable tools for prognosis, remain major unmet needs in their clinical management and for the design and interpretation of therapeutic clinical trials, particularly those aimed at disease-modification. Neurofilament light chain (NfL), a structural protein of the neuronal cytoskeleton released into cerebrospinal fluid (CSF) and blood after axonal injury, has emerged as a valuable biomarker in this context. Markedly elevated NfL levels are consistently found in MSA and PSP compared to PD, correlating with disease severity, brain atrophy, and survival. Although NfL has strong diagnostic and prognostic value at the group level, it marginally discriminates MSA from PSP as we show in this literature review and new analysis of our Barcelona cohort. Furthermore, NfL is influenced by age, comorbidities, and analytical variability. The correlation between its levels in CSF and blood, while consistently replicated, remains moderate, and their associations with clinical outcomes and disease progression are yet to be fully defined. This review summarizes current evidence on the role of NfL in MSA and PSP, covering its applications in diagnosis, prognosis, clinical trials, and real-world practice, as well as outlining the main challenges and future directions for its broader clinical translation.</p>