Abstract The inhibition of telomerase function in cancer cells via induction of a higher-order four-stranded quadruplex arrangement in the telomeric DNA substrate, requires the participation of a quadruplex-stabilizing ligand. We showed several years ago that certain metal complexes could fulfil this role and not only have selectivity for a quadruplex arrangement but had significant biological activity. We now report on the crystal structures of square-planar nickel (II) and copper (II) complexes containing salphen ligands with a human telomeric quadruplex. The structures show that the metal complexes are bound on an external G-quartet face of the quadruplex, and that the metal itself is positioned above the potassium-containing ion channel of the quadruplex, providing important stabilization. The planar groups of the ligand are stacked onto guanine bases, and the charged amino side-chains are positioned in the grooves of the quadruplex. These features are enabling the available structure-activity data to be rationalized and will be discussed in terms of the design of future complexes with enhanced activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2326. doi:10.1158/1538-7445.AM2011-2326