Mutations in some subunits of the basal DNA repair and transcription factor II H (TFIIH) are involved in several human genetic disorders. Transcription factor II H interacts with a variety of factors during transcription, including nuclear receptors, tissue-specific transcription factors, chromatin remodeling complexes and RNA, suggesting that, in addition to its essential role in transcription initiation, it also participates as a regulatory factor. Interpretation of the phenotypes produced by mutations in TFIIH is complicated by the recent finding that TFIIH plays a role in RNA polymerase I (RNA Pol I)-mediated transcription. In vitro reconstituted systems and genetic analysis suggest two possible explanations for the transcriptional phenotypes of TFIIH mutations that are not mutually excluding. The first is that different sets of genes require different levels of transcription to maintain a wild-type phenotype. The second suggests that mutations in TFIIH produce specific phenotypes arising from differential interactions of this complex with different transcription regulatory factors.