In the current competitive industrial context, enterprises must react swiftly to the market changes. In order to face this problem, enterprises must increase their collaborative activities. This implies, on the one hand, high communication between their information systems and, on the other hand, the compatibility of their practices. An important amount of work must be performed towards proper practices of standardization and harmonization. This can be defined as the concept of interoperability. Interoperability of enterprises is a strategic issue, caused, as well as enabled, by the continuously growing ability of integration of new legacy and evolving systems; in particular, the context of networked organizations of the reconciliation of the communicated business semantics is crucial to success. For this, nondisruptive reuse of existing business data stored in “legacy” production information systems is an evident prerequisite. In addition, the integration of a methodology, as well as the scalability, of any proposed semantic technological solution are equally evident prerequisites. Yet on all accounts current, semantic technologies as researched and developed for the so-called Semantic Web may be found lacking. Still, semantic technology is claimed about to become mainstream, as it is promoted by enterprise interoperation needs and increasing availability of domain specific content (for example ontologies) rather than pulled by basic technology (for example OWL) providers. In this chapter, we will present a methodology, which has resulted in the implementation of a highly customizable collaborative environment focused to support ontology-based enterprise interoperability. An additional key issue addressed by the particular platform is the variety and number of different resources that concur to achieve a cross-enterprise business service. A second key issue is the diversity of agreed (e.g., meaning negotiation when creating online contracts) models, and the difficulty in adapting its integrated features and services to different situations. These problems are addressed with a flexible solution, voiding rigidity that occurs in the implementation and maintenance of existing cooperation platforms and their integration with an advanced semantic repository. The proposed platform operates at two levels: at the front end, it enables the end users to access seamless collaborative (e.g., synchronous, asynchronous, and semisynchronous), as well as individual mode tools and services to extract valuable information; at the back end, it uses a sophisticated ontology framework to support and record the collaborative work, enhancing interoperability among different enterprises and other service providers.