Transcription of protein coding genes by RNA polymerase II is directed by a multiprotein complex that includes gene-specific enhancer binding factors and basal transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH). In vitro, basal transcription factors are sufficient to direct a low level of transcription from a core promoter, but enhancer binding factors and their DNA binding sites are required to achieve a higher level of transcription, termed activated or regulated transcription. Protein-protein interactions between the activation domains of enhancer binding factors and one or more subunits of TFIID mediate activated transcription in vitro. TFIID is a multiprotein complex composed of TATA-binding protein (TBP) and at least eight TBP-associated factors (TAFs). Specific TAFs bind different classes of activators (such as acidic, glutamine rich, or isoleucine rich). In addition, TAFs contact other components of the transcriptional machinery, recognize and contact specific DNA sequences in core promoters, and have enzymatic activities that may contribute to gene-specific transcriptional activation in vivo. We have isolated mutations in several Drosophila TAFs in a screen for genes that dominantly modify a rough eye phenotype caused by a transgene expressing a gain-of-function form of the Ras1 GTPase. TAF mutations reduce the level of transcription of the Ras1 transgene as well as transcription from other, but not all, RNA polymerase II genes. Drosophila was originally chosen as the model organism to study the role of TFIID and TAFs in transcriptional regulation because it is amenable to biochemical, molecular, and genetic approaches, and it displays complex developmental and tissue-specific transcriptional regulation. The establishment of this sensitized genetic system in Drosophila presents the opportunity to probe in vivo roles for TAFs and, in combination with the wealth of biochemical data on TAFs, to decipher the molecular mechanisms controlling transcriptional activation.