Multiple system atrophy (MSA) is a rare neurodegenerative disorder with very low incidence and prevalence worldwide. Clinically, it presents as a heterogeneous combination of autonomic failure, Parkinsonism and cerebellar ataxia. This review synthesizes current evidence on the epidemiology, subtype distribution, natural history and prognostic modifiers of MSA, with particular emphasis on the prodromal phase (e.g., rapid eye movement sleep behavior disorder and pure autonomic failure), hallmark clinical milestones after diagnosis (e.g., recurrent falls, wheelchair dependence, dysphagia, and inspiratory stridor), and key determinants of disease progression (including age at onset, severity of autonomic involvement, motor subtype and levodopa responsiveness). The clinical features and prognostic contrasts between young-onset and late-onset MSA are examined, and the future priorities focusing on biomarker development, early diagnosis and prodromal detection, and optimization of multidisciplinary care strategies are highlighted, aiming to inform clinical practice and interventional research.