RNA polymerase II initiates transcription at specific DNA sequences. Studies using sequence analysis and molecular genetics suggest a simple and universal model of start-site selection by RNA polymerase II. Two consensus sequences occur at fixed positions in promoters from higher eukaryotes and their viruses: the TATA box around -30 and the initiator at the start site of transcription. Both consensus sequences function as positioning elements that control site-specific initiation. As a first step during initiation, the basal transcription factor TFIID binds to the TATA box; regulatory transcription factors can tether TFIID bind to the TATA box; regulatory transcription factors can tether TFIID to promoters without a consensus TATA box. TFIID then directs the assembly of other basal transcription factors and RNA polymerase II into a preinitiation complex. Finally, RNA polymerase II searches for the best match to the initiator consensus about 30 base pairs downstream of the TATA box to select the exact start site. The transcriptional activity of a start-site sequence generally correlates with its similarity to the initiator consensus, suggesting that there is only one type of initiator.