Abstract Semantic interoperability is one of the great challenges in biomedical informatics. Methods such as ontology alignment or use of metadata neither scale nor fundamentally alleviate semantic heterogeneity among information sources. In the context of the Cancer Biomedical Informatics Grid program, the Biomedical Research Integrated Domain Group (BRIDG) has been making an ambitious effort to harmonize existing information models for clinical research from a variety of sources and modeling agreed-upon semantics shared by the technical harmonization committee and the developers of these models. This paper provides some observations on this user-centered semantic harmonization effort and its inherent technical and social challenges. The authors also compare BRIDG with related efforts to achieve semantic interoperability in healthcare, including UMLS, InterMed, the Semantic Web, and the Ontology for Biomedical Investigations initiative. The BRIDG project demonstrates the feasibility of user-centered collaborative domain modeling as an approach to semantic harmonization, but also highlights a number of technology gaps in support of collaborative semantic harmonization that remain to be filled.