THE KEY TO INTEROPERATION and therefore to computer-empowerment in biology will be a technology infrastructure that supports the development and use of a repertoire of pragmatically driven, longitudinally maintained, terminology models that “explain biology to computers.” Called “Reference Terminology Models,” these resources name and relate concepts such as sequences, structures, and functions, in a way that computers can exploit on behalf of biologists. Thus, a computer can use an appropriate reference terminology to help it determine if a given represented concept in one computer is equivalent to or related to a represented concept in another computer. The computer science challenge is the creation of an infrastructure that supports the productive creation, deployment, maintenance, evolution and use of Reference Terminology Models. In short, such models will be successful only if they are part of a supported, scalable, longitudinal process, and the process needs to be supported technologically. Such an infrastructure would create much of what would be required for a Semantic Web for biology.