The devastating genetic disorder Cockayne syndrome (CS) arises from mutations in the CSA and CSB genes. CS is characterized by progressive multisystem degeneration and is classified as a segmental premature-aging syndrome. The CS complementation group B (CSB) protein is at the interface of transcription and DNA repair and is involved in transcription-coupled and global genome–DNA repair, as well as in general transcription. Recent structure-function studies indicate a process-dependent variation in the molecular mechanism employed by CSB and provide a starting ground for a description of the mechanisms and their interplay.