The ubiquitination of a protein may promote proteasomal degradation, protein–protein interactions, lysosomal degradation or intracellular trafficking. Transcription factors are targets for ubiquitination by E3-ligase proteins, which results in the regulation in their function. The degradation of transcription factors enables the rapid regulation of gene expression by the ubiquitin–proteasome system. Underlying this system is the integration of multiple intracellular signaling networks that result in specific patterns of transcription. In this review we will discuss the regulation of transcription machinery, cofactors, histones and transcription factors by the ubiquitin–proteasome system and discuss the complex interplay between other posttranslational modifications that regulate gene expression. Finally, we will consider the implications of ubiquitin–proteasome system regulation of transcription in neurological disease states.