BACKGROUND: A precise temporal and spatial regulation of gene expression is necessary to achieve neural tube closure. Med12, a subunit of the mediator complex, can bind transcription factors and modulate expression of their target genes. Med12 is essential during early mouse development and is important for neural tube closure. METHODS: We have made use of a mouse line carrying a conditional null allele of the X‐linked Med12 gene to generate heterozygous female embryos that express Med12 in a mosaic fashion thus allowing the study of the role of Med12 during neural tube closure. RESULTS: Mosaic expression of Med12 causes a wide variety of embryonic phenotypes. Some embryos were unable to complete turning and were found with arrested development at embryonic day (ED) 9.5. Others were able to pass ED 12.5 and displayed defects in neural tube closure. These defects included exencephaly, spina bifida, craniorachischisis, split face, and curly tail. Histologic and skeletal analyses of these mutant females show that the neural plate is unable to elevate and is completely flat in the regions of the body axis where neural tube closure fails. CONCLUSIONS: We report examples of all known neural tube defects implying Med12 in the full process of neural tube closure along the complete body axis. Our work points to Med12 being an essential coregulator of transcription factors controlling neural tube closure. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.