Cells use transcription factors to regulate specific gene expression patterns in response to developmental and environmental cues. The factors form specialized multi-protein complexes to regulate expression at promoters of genes involved in regulating cellular responses. Transcription factors with aberrant activity in disease are promising yet untested targets for therapeutic development. 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 challenging and the protein class is often perceived to be recalcitrant or “undruggable.” Groups in the Chemical Biology Program combine novel high-throughput binding assays with cellular and transcriptional assays to identify direct probes of transcription factors involved in disease. For example, several collaborative projects are underway aimed at developing probes for latent cytoplasmic transcription factors having increased activity in most human cancer cancers such as the STATs and NF-κB. We use a similar approach to discover small molecules that selectively target and modulate aberrant transcriptional regulators arising from oncogenic chromosomal translocations involving transcription factors. Our success would have implications for (1) our understanding of appropriate molecular features or chemotypes for modulating proteins that function primarily through interactions with other proteins or DNA, (2) development of probes for understanding the role of transcription factors in various cancers and (3) development of therapeutic leads for diseases of aberrant transcription.