USP22, a component of the SAGA complex, is overexpressed in highly aggressive cancers, but the normal functions of this deubiquitinase are not well defined. We determined that loss of USP22 function in mice results in embryonic lethality between E12.5 and E14.0 due to defects in extraembryonic placental tissues that result in a failure to establish proper vascular interactions with the maternal circulatory system. These defects correlate with abnormal gene expression patterns that reflect defective receptor kinase signaling, including TGF-beta and RTK pathways. As these same pathways are often hyperactivated in cancer, our data provide the first insights to UsP22 functions that may be tied to oncogenesis.