Transcription factors are DNA-binding proteins that – usually in combination with other proteins to form the pre-initiation complex (PIC) – regulate the transcription of specific DNA sequences (genes) into mRNA by controlling the recruitment of RNA polymerase II. Constitutive activation of transcription factors can lead to a variety of cancers, and are, therefore, important therapeutic targets. However, in stark contrast to targeting enzyme active sites, disruption of protein–protein or protein–DNA interactions involved in the transcriptional machinery is particularly challenging owing to the large interfacial areas involved, a lack of obvious binding sites and often non-contiguous contact points. Especially problematic for the development of small-molecules is the need by such agents to overcome the large free energy of association between protein–protein and, to a lesser extent, protein–DNA interfaces. Nevertheless, recent years have seen considerable success in this area of medicinal chemistry, cementing the notion that disruption of such interactions is feasible with small-molecule, drug-like compounds. We discuss, in particular, the disruption of dimeric transcription factors, such as STAT3–STAT3, c-Myc–Max and c-Jun–c-Fos (AP-1), with small-molecules that block their protein–protein interactions or their interactions with DNA.