Uterine leiomyomas, or fibroids, are benign tumors arising from the smooth-muscle layer of the uterus that can produce a range of clinical symptoms. A new study by Lauri Aaltonen and colleagues (Science, published online 25 August 2011; doi:10.1126/science.1208930) now shows that a majority of uterine leiomyomas harbor mutations in MED12, an X-chromosome gene that encodes a subunit of the Mediator complex implicated in transcriptional regulation. The authors performed exome sequencing of 18 uterine leiomyomas and matched normal tissue and found somatic mutations of MED12 in 10 tumors. Notably, all of the mutations clustered in exon 2, with eight mutations affecting codon 44. Sequencing of this region in 207 additional uterine leiomyomas identified MED12 mutations in 70% of tumors, with codon 44 altered in 49% of tumors. Previous studies have reported germline mutations at codons 961 and 1007 of MED12 as the most frequent causes of Opitz-Kaveggia and Lujan-Fryns syndromes, two rare congenital disorders that are not associated with tumor susceptibility. The clustering of MED12 mutations to exon 2 in uterine leiomyomas suggests that a distinct molecular mechanism underlies the selection for MED12 mutations in these tumors.