Cre-LoxP–based conditional activation of oncogenes is an effective strategy for generating murine models of human cancers. However, when tissue-specific Cre-expressing mice are used, Cre (and hence the oncogene) is expressed in all or most cells of the target tissue that may disrupt ‘tumor-promoting’ intercellular interactions between oncogene-expressing cells and normal cells of its surrounding microenvironment. This is a major limitation of tissue-specific Cre-based conditional strategy in tumor modeling. Haldar and colleagues describe a CreERbased strategy that circumvents this limitation and generates a new mouse model of synovial sarcoma. The cover image shows a micrograph of a synovial sarcoma–like tumor generated in mice by sporadically expressing the SYT-SSX2 oncogene across multiple tissue types. The authors compare this new model to a previously established model of synovial sarcoma to provide new insights into the underlying pathogenesis. The CreER-based strategy described here can be used to rapidly generate mouse models of other translocation-associated sarcomas. For details, see the article by Haldar and colleagues on page 3657 of this issue.