Nuclear receptors, also known as ligand-activated transcription factors, regulate gene expression upon ligand signals and present as attractive therapeutic targets especially in chronic diseases. Despite the therapeutic relevance of some nuclear receptors in various pathologies, their potential in neurodegeneration and neuroinflammation is insufficiently established. This perspective gathers preclinical and clinical data for a potential role of individual nuclear receptors as future targets in Alzheimer's disease, Parkinson's disease, and multiple sclerosis, and concomitantly evaluates the level of medicinal chemistry targeting these proteins. Considerable evidence suggests the high promise of ligand-activated transcription factors to counteract neurodegenerative diseases with a particularly high potential of several orphan nuclear receptors. However, potent tools are lacking for orphan receptors, and limited central nervous system exposure or insufficient selectivity also compromises the suitability of well-studied nuclear receptor ligands for functional studies. Medicinal chemistry efforts are needed to develop dedicated high-quality tool compounds for the therapeutic validation of nuclear receptors in neurodegenerative pathologies.