Andy van Dam's involvement with hypermedia system design began with a chance meeting with an old acquaintance. In 1967, van Dam ran into Ted Nelson at a computer conference, and found out about the hypertext ideas that Nelson had been developing. Intrigued, van Dam began to work with Nelson at Brown University on the Hypertext Editing System.

First announced to the wider world in 1969, this Hypertext Editing System had two purposes: one, to program computers to format and print linear text; and two, to develop hypertext concepts. Taking advantage of recent improvements in computer displays, the HES made extensive use of on-screen editing. It also allowed users to embed links within a text file and attach branches to the end of a text file, so that readers could easily move to related documents. It also allowed text strings to be any size rather than an arbitrary length, giving the writer greater freedom to create.

In 1968, van Dam moved on from the HES to FRESS (File Retrieval and Editing System), in which he hoped to combine the best aspect of HES and the best aspects of Doug Engelbart's recently demonstrated NLS. FRESS was notable for its system-independence, its software paging scheme (which made working with large files as quick and easy as working with small ones), bidirectional links, and an undo feature. FRESS was discontinued in the late 1970s.

In the mid-1970s, van Dam worked on a hypertext in poetry education project funded by the National Endowment for the Humanities. This system allowed students to view scholarly commentary and the marginalia of other students while they were reading their assigned poems. In the process, they could follow trails or mark their own. They could also add their own annotations, leading to an effect that van Dam approvingly called "electronic graffiti."

After the end of FRESS, van Dam moved from hypertext to hypermedia. The Electronic Document System, designed to aid the production of graphical documents, had three subsystems: the Picture Layout System, the Document Layout System, and the Document Presentation System (this tripartite division between presentation, semantics, and structure continues in 1998 and for the foreseeable future on the World Wide Web, with the use of CSS, XML, and HTML as interlocking standards). The user interface for the system was itself graphical, and included a hypertext component in which users could construct pages, chapters, and links while viewing their entire system graphically. The project also gave users the power to view their documents at varying levels of detail. This project closed down in 1982.

In 1983, van Dam helped set up the Institute for Research on Information and Scholarship at Brown University. IRIS specialized in designing scholarly tools to take advantage of the increasing power of personal workstations. Van Dam and his students (most notably Nicole Yankelovich and Norman Meyrowitz) spent the mid-1980s exploring ways to use workstations as a medium for "electronic books" (hypertexts whose content and display values are dynamic) and designing a new generation of hypertext systems.

That new generation -- van Dam's fourth in 20 years -- was called Intermedia, and was unveiled to the public in stages between 1985 and 1987. Intermedia was an all-purpose hypertext system, containing not just a hypertext engine but also editors for text, graphics, scanned images, and timelines. Intermedia made extensive use of the then-new Macintosh interface standards (including its desktop metaphor) as well as incorporating object-oriented programming concepts such as reusable code, classes, and hierarchical inheritance.