<p>Recent advancements have seen several new possibilities and challenges in nucleic acid structural polymorphism extending beyond the conventional Watson-Crick DNA duplex structure. Triplexes, G-quadruplexes, i-motifs, DNA junctions, and other non-canonical secondary structures are increasingly recognized as critical mediators in gene regulation, genomic stability, and disease progression. These structures present unique molecular recognition sites for exogenous ligands, proteins, metal ions, particularly metal complexes, underscoring their therapeutic potential. While metal-based drugs have long been used in therapeutics, the general non-specificity of metal complexes leads to off-target interactions, reduced efficacy, acquired resistance, and increased side effects. These interactions involve serious side effects such as neurotoxicity, systemic toxicity that limit their widespread clinical applications. The limited understanding of diverse topologies necessitates the development of more selective and efficient alternatives. Tuneable structural features like size, charge, planarity, ligand flexibility, and stereochemistry may facilitate selectivity to match unique topology of diverse multi-stranded DNA structures. Recent literature highlights a Pt (II) and Ru (II) complexes with high specificity for G-quadruplexes (e.g., K_a = 5.2 × 10⁵ M⁻¹ for Pt (II) dinuclear on <i>c-</i><i>MYC</i> G-quadruplex, more than 10-fold over duplex), while triplex-stabilizing PNAs show a K_a up to 2.2 × 10⁸ M⁻¹ for purine-bulged structures, with ΔTm &gt; 10&#xa0;°C. This review primarily explores the structural dynamics of multi-stranded DNA and the design of metal complexes for topology-specific recognition. It also looks to highlight binding mechanisms, challenges in selectivity, and applications in diagnostics, therapeutics, and nanotechnology. This thorough analysis may further enhance our knowledge of nucleic acids as molecular tools which can help in developing more specific and efficient metal-based drugs.</p>