Ets family transcription factors, characterized by an evolutionary conserved Ets domain, play important roles in cell development, cell differentiation, apoptosis and tissue remodeling. All members of this family have an activation or a repression domain for DNA binding. The Ets domain has been shown to bind 5-GGAA/T-3 core motif of DNA by its wHTH (winged helix-turn-helix) structure, as determined by NMR or X-Ray crystallography analysis. A number of Ets transcription factors have been shown to be involved or directly implicated in the pathogenesis of a wide spectrum of human cancers. They are thus potential molecular targets for selective cancer therapy. Computer simulations using molecular dynamics allows monitoring the dynamics of individual atoms, thereby giving a unique insight into the structural flexibility of binary complexes between Ets-domain and a specific DNA sequence that cannot be easily extracted from laboratory experiments. Moreover, an understanding of structural motifs that influence the specificity of Ets domains is essential for antitumor drug design. Here we describe molecular and structural studies that provide a detailed description of the direct and indirect readout mechanisms of DNA recognition by Ets domains, a conserved mechanism observed in other DNA-protein complexes.