MED14 is a core subunit of the Mediator complex, a 26-subunit coactivator that bridges gene-specific transcription factors to RNA polymerase II (Pol II) transcription machinery 1. MED14's N-terminal domain directly interacts with the RPB1 subunit of Pol II and is essential for recruiting Pol II to core promoters and facilitating both basal and activated transcription 2. Structurally, MED14 participates in preinitiation complex (PIC) assembly, where Mediator reorganization creates a Head-Middle sandwich stabilizing Pol II's C-terminal domain for CDK7-mediated phosphorylation 1. MED14 mediates gene-specific transcriptional regulation through differential cooperation with other Mediator subunits; for example, glucocorticoid receptor-dependent gene induction requires both MED14 and MED1 for some targets but only MED14 for others 3. MED14 also regulates enhancer landscape activation in mammary stem cells, where XIST-mediated X-inactivation normally silences MED14; loss of XIST causes MED14 overexpression, hyperactivation of cell identity programs, and increased tumorigenicity 4. Clinically, pathogenic MED14 variants cause X-linked immunodeficiency characterized by impaired T cell development while preserving B and NK cells 5. MED14 dysfunction also contributes to broader "MEDopathies"—neurodevelopmental and neurodegenerative disorders featuring developmental delay, intellectual disability, epilepsy, and characteristic neuroradiological abnormalities including callosal defects and hypomyelination 6. Additionally, MED14 supports HIV-1 transcription and viral replication 7.