Traditional drug discovery relied on animal models (a "black box" with unclear mechanisms) and later shifted to a "one-target, one-disease" paradigm, but many diseases remain inadequately treated. This has driven interest in polypharmacology—modulating multiple targets to enhance efficacy or improve safety—via three approaches: drug cocktails, multicomponent drugs, and designed multiple ligands (DMLs). DMLs are rationally designed to target multiple disease-relevant pathways, distinct from nonselective ligands that cause side effects. Compared to multicomponent drugs, DMLs have similar clinical development risks as single entities, lower drug-drug interaction risks, but require early-stage design complexity to balance target activities. Design strategies include knowledge-based (combining structural elements from selective ligands) and screening (high-throughput/focused screening). DMLs are categorized as conjugates (linked pharmacophores via a linker), fused (partially merged frameworks), or merged (highly integrated structures). Key challenges include balancing target activity ratios, optimizing pharmacokinetics/physicochemical properties for oral absorption, and minimizing off-target effects. Examples span psychiatric (dual D2/5-HT2a antagonists), antidepressant (SERT/5-HT1A ligands), anti-inflammatory (COX-2/5-LOX inhibitors), and oncology (kinase inhibitors like imatinib derivatives) applications. DMLs represent an emerging drug discovery paradigm with potential to overcome single-target limitations, though design and optimization hurdles persist.