Mediator is an essential component of the RNA polymerase II-mediated transcription machinery. This component plays a key role both in the stimulation of basal transcription and in the regulation of eukaryotic mRNA synthesis. The Saccharomyces cerevisiae Mediator complex was the first to be studied and consists of at least 20 different subunits with multiple activities. Afterwards, its subunit composition was determined and related functions of C. elegans, Drosophila and mammalian complexes show a striking evolutionary conservation both of the structure and function from yeast to man. Recently, yeast studies strongly suggest additional roles for Mediator in coordinating transcription initiation with downstream transcriptional events in the coding region of genes; consequently, new models of recruitment-coupled regulation have been indicated. Further studies on transcription machinery should expand our knowledge of the pathways in which variant components of Mediator, or variant proteins interacting directly or in complexes, represent risk factors for complex inheritable disease.