Programming transcription In a cell’s intricately regulated gene expression network, transcription factors (Tfs) call the shots. If we fully understood how Tfs operate, not only would we understand gene regulation but we could also use this understanding to engineer gene circuits for biotechnology purposes. Khalil et al. took a step in this direction. They constructed synthetic Tfs consisting of a zinc-finger domain that binds a user-specified sequence within an engineered promoter, an activation domain that recruits the transcription machinery and a protein-protein interaction domain that interacts with other Tfs. The researchers created a library of such Tfs and engineered cooperative transcriptional systems in yeast that use the multimerization of weak Tfs to fine-tune expression levels. These modular complexes are more like their natural counterparts, and the synthetic recapitulation of transcriptional regulation will allow insights into how a cell regulates its transcription. Khalil, A.S. et al. Cell 150, 647–658 (2012).