Alzheimer's and Parkinson's disease (AD/PD) are age-related, devastating neurological disorders both characterized by accumulation of amyloidogenic proteins in diseased brains. Pathological hallmarks of AD are extracellular amyloid plaques and intraneuronal tangles consisting of noxious, misfolded a-beta peptides and hyperphosphorylated protein tau respectively, whereas α-synuclein is misfolded and deposited into the typical Lewy bodies in the PD brain. Therefore, inhibition of the development of these cytotoxic misconformers may represent an effective therapeutic intervention for both neurodegenerative diseases. Unlike the conventional, high-risk/high-cost single-target-based approach in drug discovery – which is unlikely to intervene complex, multi-factorial protein-misfolding disorders – reMYND developed an HTS-platform in which small molecules are screened in yeast-based models of tau and α-synuclein protein misfolding, aggregation and cytotoxicity. Since efficacy of compounds in this “biology”-driven approach are judged in a physiologically and pharmacologically relevant way, cell-based screenings represent an excellent tool for development of first-in-class disease modifying drugs. Primary hits are confirmed and optimized in neuronal-based assays of protein-aggregation toxicity. Lead optimization towards potent and safe drug candidates has resulted in 3 highly active families of small molecules (ReS9-T, ReS3-T and ReS9-S) with cytoprotective properties in human neuronal cell models of AD and PD. In vivo studies in hAPP and hTAU transgenic mouse models for AD revealed a potent activity of the ReS9-T and ReS3-T lead molecules on amyloid plaque-load and tau-aggregation respectively. The ReS9-S lead was found to inhibit or delay motoric impairment in a hSYN transgenic PD-like mouse model in addition to a complete protection against paraquat-induced nigro-striataldopaminergic degeneration in mice. Collectively, biology-driven drug discovery using cellular models of protein misfolding has resulted in the identification of novel chemical entities that counteract associated neurotoxicity and modulate classical hallmarks of neurodegenerativedisease.