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The molecular mechanisms underlying tau toxicity and neurodegeneration in these diseases are still poorly understood. Proteomics studies of human primary tauopathy brain tissue are beginning to provide insight into molecular mechanisms involved in disease pathogenesis. Here, we review the current landscape of human brain proteomics in three primary tauopathies: progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. For progressive supranuclear palsy, the most well\u2010studied primary tauopathy, we provide a combined analysis of bulk proteomic changes in the brain. From this compilation and additional studies using complementary proteomics approaches, we highlight five highly relevant disease mechanisms in primary tauopathies: mitochondrial dysfunction, synaptic impairment, autophagy and endolysosomal dysfunction, RNA and RNA\u2010binding protein dysregulation, and iron dyshomeostasis. 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