Binding of transcription factors to functional sites is a fundamental step in transcriptional regulation. In this chapter, we discuss how transcription factors are thought to achieve specificity to their functional targets, despite their typically low concentrations and degenerate binding specificities, and the fact that in large genomes their functional binding sites must compete with their widespread alternative binding sites. We highlight the importance of the chromatin structure context of the binding sites in this process, and its dependency on the genomic DNA sequence.