Gene-specific transcription factors are DNA binding proteins that function at the center of the transcriptional machinery to mediate the cellular phenotype in response to extracellular signals. Owing to the lack of enzymatic activities of these intracellular proteins, manipulating the activity of transcription factors by small organic molecules is widely considered to be a difficult task. In this review, I will discuss general approaches designed to inhibit a subset of transcription factors, referred to as dimeric transcription factors, by cell-permeable small organic molecules that inhibit protein–protein interactions or protein–DNA interactions. These dimeric transcription factors include hypoxia-inducible factor (HIF)-1, c-Myc, and signal transducer and activator of transcription (STAT) 3. The data presented here indicate that dimeric transcription factors can be potently and selectively inhibited by drug-like small molecules.