Multiple system atrophy (MSA) is an atypical parkinsonism that rapidly affects motor ability and autonomic function, leaving patients wheelchair-bound and dependent for daily activities in 3-5 years. Differential diagnosis is challenging as cases may resemble Parkinson’s disease or other ataxic syndromes depending on the clinical variant (MSA-P or MSA-C), especially in early stages. There are limited symptomatic treatments and no disease-modifying therapies. Pathologically, alpha-synuclein aggregates are found in glial cytoplasmic inclusions, among other proteins, as well as in neurons. The molecular pathogenesis of the disease, however, is widely unknown. Transcriptomic studies in MSA have tried to unravel the pathological mechanisms involved in the disease. Several biological and molecular processes have been described in the literature that associate disease pathogenesis with inflammation, mitochondrial, and autophagy related dysfunctions, as well as prion disease and Alzheimer disease associated pathways. These reports have also registered several differential diagnostic biomarker candidates. However, cross-validation between studies, in general, is poor, making clinical applicability and data reliability very challenging. This review will go over the main transcriptomic studies done in MSA, reporting on the most significant transcriptive and post-transcriptive changes described, and focusing on the main consensual findings.Copyright © 2020 Elsevier B.V. All rights reserved.