Abstract: Mammalian Mediator is a key coactivator that enables transcriptional activators to regulate transcription by RNA polymerase II (pol II). Like the yeast complex to which it is phylogenetically related, it contains up to 30 subunits. These subunits are organized as a tightly associated core sub-complex, which associates with several groups of subunits that might constitute distinct modules. Although the complex seems to be universally required at all genes, specific subunits are dedicated to regulation of distinct expression programs via interactions with relevant gene-specific transcriptional activators. These interactions, in conjunction with dynamic effects of the core complex on pol II and the general transcription factors, lead to activation of transcription at the target gene. In addition, the compositional complexity of the Mediator allows for assimilation of other diverse signals such as those emanating from repressors and other coactivators.