Prolyl isomerases are ubiquitous in biology. They help in the folding of newly-synthesized proteins and are increasingly recognized for their role in regulating the activity of mature proteins. They work by inducing conformational changes in protein structure, and function in processes as diverse as membrane permeability, HIV infection and transcription regulation. The Ess1 prolyl isomerase, which we discovered, targets the CTD of RNA polymerase II and controls recruitment of co-factors required for eukaryotic transcription. Mutations in the yeast Ess1 are lethal and mis-expression of its human ortholog (Pin1) is reported to be associated with numerous diseases including cancer and neurodegenerative disease. I will describe the structure and function of Ess1 as an example of how prolyl isomerases can affect enzyme activity, assembly of protein complexes and transcription efficiency. If time permits, I’ll describe our studies of Ess1 in pathogenic fungi and the discovery of additional targets of Ess1.