Interoperability has been a basic requirement for the modern information systems environment for over two decades. How have key requirements for interoperability changed over that time? How can we understand the full scope of interoperability issues? What has shaped research on information system interoperability? What key progress has been made? This chapter provides some of the answers to these questions. In particular, it looks at different levels of information system interoperability, while reviewing the changing focus of interoperability research themes, past achievements and new challenges in the emerging global information infrastructure (GII). It divides the research into three generations, and discusses some of achievements of the past. Finally, as we move from managing data to information, and in future knowledge, the need for achieving semantic interoperability is discussed and key components of solutions are introduced.