Abstract: Prokaryotic transcription can be recapitulated largely with a four-subunit RNA polymerase and naked DNA. By contrast, eukaryotic transcription requires a chromatin template, large multiprotein chromatin-remodeling and -modifying complexes, a 12-subunit RNA polymerase (for protein-coding genes), five general transcription (initiation) factors (individually comprising as many as nine subunits), a 20-subunit Mediator complex, diverse elongation factors, and a multitude of gene-specific regulatory proteins and accessory factors. This vast complexity enables the regulated transcription of tens of thousands of genes in higher organisms, and underlies development and cell differentiation. Discovery of the many dozens of eukaryotic transcription proteins has been the work of a generation of scientists in many laboratories across the world. Much remains uncertain, but due to key connections made in the past few years, a coherent picture has begun to emerge. A series of reviews on transcription factors beginning with that by Workman and co-workers on page 15 of this issue mark this watershed in transcription research. The reviews will be illustrative rather than comprehensive. The thousands of gene-specific transcription factors that bind to enhancer, operator and silencer elements in the genome will be represented by a few well-studied examples. Several reviews will describe the current excitement surrounding so-called cofactors, the chromatin-remodeling and -modifying complexes, and the giant Mediator that conveys regulatory information from enhancers and operators to promoters. Finally, there will be a review on the much-debated role of the transcription-initiation factor TFIID, and a review on the less-investigated but no-less-fascinating and important topic of elongation factors. As will become apparent from this series of reviews, no single solution has been found to the mystery of eukaryotic transcriptional regulation. Rather, regulation occurs at every step of the pathway from a physiologic signal to the appearance of a complete transcript. Gene-specific factors can be controlled by conversion to an active state and by translocation to the nucleus. Chromatin – through its fundamental subunit, the nucleosome – exerts a general negative-regulatory effect, accounting for the extinction of most gene expression in most cell types and enabling the broad specificity of the gene-activation process. Transcription per se starts with the processing and transmittal of regulatory information by Mediator to RNA polymerase, whereas completion of the transcript is controlled by elongation factors. A key area for future transcription factor research will be structural studies, at two levels, the higher-order organization of eukaryote chromosomes and high-resolution structural detail of the transcription machinery. Due to the vast size of the multiprotein complexes involved, these structural studies present a daunting challenge, which must be met for a full understanding of transcription factor biology to be achieved.