Our understanding of the pathogenesis of diseases has advanced enormously in recent decades, leading drug discovery to shift from a human phenotype-based endeavor to a reductionist approach centered on single molecular targets. However, single-target drugs may be inadequate for multifactorial diseases like neurodegenerative syndromes. Therapy with a single drug having multiple biological properties (multi-target-directed ligands, MTDLs) offers inherent advantages over multiple-medication therapy (MMT) or multiple-compound medication (MCM), such as obviating the challenges of administering multiple single-drug entities with different bioavailability, pharmacokinetics, and metabolism, avoiding drug-drug interactions, and simplifying therapeutic regimens. Thus, developing compounds able to hit multiple targets might disclose new avenues for the treatment of major neurodegenerative diseases, for which an effective cure is an urgent need and an unmet goal. The objective of this Perspective is to review those investigations reported in the past decade that illustrate the ability of medicinal chemists to design MTDLs to confront neurodegenerative diseases. We will briefly illustrate the multifactorial nature of these diseases before discussing the possible development of MTDLs in light of the known molecular bases of the main neurodegenerative pathologies.