The ability to program molecules to bind to specific sequences of DNA with high fidelity and stability is an important goal of chemical biology. Such molecules can compete with transcription-factor proteins and thus modulate the transcription of genes. They are therefore promising for both elucidating the complex regulation of mammalian gene expression, and developing pharmaceuticals and medical diagnostics targeted to genetic abberations. Writing in Nature Chemistry, Brent Iverson and co-workers have now described the excellent sequence specificity and unusual binding kinetics of a stable DNA–ligand complex, which exhibits a half-life of 16 days.