Transcription factors with aberrant activity in disease are promising yet untested targets for therapeutic development, particularly in oncology. Directly inhibiting or activating the function of a transcription factor requires specific disruption or recruitment of protein–protein or protein–DNA interactions. The discovery or design of small molecules that specifically modulate these interactions has thus far proven to be a significant challenge and the protein class is often perceived to be ‘undruggable.’ This review will summarize recent progress in the development of small-molecule probes of transcription factors and provide evidence to challenge the notion that this important protein class is chemically intractable.