Biological processes are mediated by specific interactions between cellular molecules (DNA, RNA, proteins, etc.). The molecular identification mark, or signature, required for precise and specific interactions between various biomolecules is not always clear, a comprehensive knowledge of which is critical not only for a mechanistic understanding of these interactions but also for therapeutic interventions of these processes. The biological problem we will address here, stated in general terms, is: how do biomolecules accurately identify their binding partners in an extremely crowded cellular environment? An important class of cellular interactions concerns the recognition of specific DNA sites by various DNA binding proteins, e.g. transcription factors (TF). Precisely how the TFs recognize their DNA binding sites with high fidelity is an active area of research. While a detailed treatment of this question covers several areas of investigation, we will focus on aspects of the TF–DNA recognition signal that is encoded in the DNA binding site itself. In this chapter we will summarize a number of approaches to model DNA sequence signatures recognized by transcription factor proteins.