Zinc finger proteins form a ubiquitous family of transcription factors—proteins that bind DNA in a sequence-specific manner and regulate gene expression. They have a remarkable modularity, which allows mixing and matching of up to six DNA binding domains, fostering highly specific targeting of a diverse set of DNA motifs. Because of this feature, zinc fingers hold great promise as tools for the precise control of gene regulation and have potentially numerous and profoundly important medical applications (Klug, 2005). The design of engineered zinc fingers for practical applications requires a thorough understanding of the interaction “code” that defines transcription factor/DNA binding specificity. Deciphering this code brings together structural analysis with bioinformatics and ab initio computational modeling studies (Paillard et al., 2004). The figure shows the structure of the transcription factor protein Zif268 (blue) containing three zinc fingers in complex with DNA (orange). SOURCE: Pavletich and Pabo, 1991; reprinted with permission from the American Association for the Advancement of Science.