Transcription factors are recognized as the master regulators of gene expression. Interestingly, about 10% of the transcription factors described in mammals are up to date directly implicated in a very large number of human diseases. With the exception of ligand-inducible nuclear receptors, transcription factors have longtime been considered as “undruggable” targets for therapeutics. However, the significant breakthroughs in their protein biochemistry and interactions with DNA at the structural level, together with increasing needs for new targeted-approaches particularly in cancers, has changed this postulate and opened the way for targeting transcription factors. Along with a better knowledge of their specific DNA binding sequences by genome wide and high throughput sequencing assay, these informations make possible the potent targeting of the transcription factors by three approaches dependently of their mechanism of action. In this review, we discuss the different physicochemical interactions between the transcription factors and the DNA helix, and the protein/protein interactions within a transcription factor complex and their impacts on the DNA structure. In order to impair transcription factor activities, small molecules compounds can either act by direct interaction on the transcription factor, or by blocking the protein/protein interactions in a transcription complex, or by competing with the transcription factor itself and specifically targeting its cognate binding sequence. For this latter mode of transcription targeting, we pay special attention to the DNA intercalating, alkylating or groove binders for transcription factor/DNA binding modulation.