The identification of active interventions in neurodegenerative disorders is a major challenge in neurology; the use of repurposed drugs may represent a valuable strategy. Tetracyclines, a second generation of antibiotic molecules, offer various potential applications. Following an anecdotal observation of the potential anti-amyloidogenic activity of iododoxorubicin, the search for chemical analogs with a better safety profile led to tetracyclines. Their heterocyclic structures with a planar conformation interfere with b-sheet amyloid formation. Thus, doxycycline, a derivative with favorable blood-brain barrier penetration, emerged as a strong candidate to combat peripheral and central amyloidosis. In particular, we tested the anti-prion activity of doxycycline in vitro and in vivo experiments, confirming its capacity to disrupt or inhibit the formation of prion protein aggregates associated with pathological events. Treatment with doxycycline in human subjects with prion - related encephalopathies yielded contradictory results, suggesting that a preventive approach is a more favorable condition to verify efficacy; a clinical trial involving subjects at genetic risk of developing fatal familial insomnia, exposed to doxycycline for ten years, is currently ongoing. The anti-amyloidogenic capacity of doxycycline, combined with its safety profile in long-term treatment, has suggested its use in peripheral amyloidosis, which was tested with positive results. A specific interaction with β-amyloid or α-synuclein oligomers, as well as tau aggregation has also been demonstrated. More recently, the action of doxycycline has been extended to its anti-inflammatory and antioxidant capacities. In particular, the anti-inflammatory activity of doxycycline may explain the drug 's efficacy in numerous experimental models where protein misfolding has been associated with neuroinflammation, including Huntington's and Parkinson' s diseases. Thus, the pleiotropic action of doxycycline appears to be an interesting tool for addressing progressive neuronal dysfunction in multifactorial neurodegenerative diseases. The application of precision medicine principles to doxycycline treatment represents the best strategy to determine its efficacy. These aspects are illustrated here concerning another pleiotropic tetracycline, minocycline.