We are interested in the molecular events that unfold when genes are switched on inside living cells. To activate a gene, the information in its DNA must first be transcribed into molecules of RNA—a task carried out by the enzyme RNA polymerase II. The activity of this enzyme has been studied primarily in test tubes, and surprisingly little is known about how the polymerase locates and activates its target genes inside the crowded nucleus of living cells. As a postdoctoral fellow, I discovered that RNA polymerases transiently form clusters in human cells. Recently, my laboratory found that these clusters of about 100 molecules form for about 10 seconds at the site of a gene that is to be activated, and the cluster duration correlates with how many RNA molecules are transcribed. Now, using a combination of techniques in cell and molecular biology, biochemistry, genomics, and “super-resolution” imaging of live cells, we will determine which portion of the polymerase mediates clustering and catalog which genes rely on these clusters for their activation. These findings will deepen our understanding of one of life’s most fundamental processes—decoding our genetic information—disruptions in which are linked to many human diseases, including most cancers.