Many of the dynamic changes in gene expression that occur in response to extracellular signals are mediated by post-translational modifications that regulate the activity of promoter-specific transcription factors. A number of transcription factors have been found to be modified by covalent attachment of the small ubiquitin-related modifier, SUMO. Several enzymes that promote either the addition or removal of SUMO have now been identified and shown to impact transcription factor activity. Recent studies provide new insights into how post-translational modification by SUMO regulates gene expression by altering transcription factor stability, localization, DNA binding, and activation.