The Mediator complex is a fluid assemblage of approximately 25 proteins that is essential for eukaryotic transcriptional regulation. Mediator of RNA polymerase II transcription (MED)12 (HOPA) is a 25-kb Xq13 member of the Mediator complex that plays a key role in the complex and directly moderates receptor tyrosine kinase, nuclear receptor and Wnt pathway signaling. Sequence variation in two MED12 protein domains has been linked to neuropsychiatric illness. First, variants in the Leu-Ser domain have been linked to Opitz-Kaveggia and Lujan syndromes, which are forms of X-linked mental retardation. Second, a balanced polymorphism in the C terminus opposite-paired domain, a key motif in the MED12-mediated transcriptional repression of Wnt signaling, has been associated with increased risk for psychosis. We conclude that variation of MED12 is associated with a wide variety of clinical presentations whose severity is dependent on the location and nature of the variation, and that a thorough understanding of MED12's role in transcriptional regulation could have significant benefits for human healthcare.