This paper discusses theory and research issues associated with the use of hypermedia technologies to support learning in problem-oriented pedagogical environments involving cases. After considering research issues with problem-oriented learning related to knowledge transfer and conceptual change, a design framework is discussed for a hypermedia system with scaffolding features designed to support and enhance problem-oriented learning. An ongoing project using a new version of this hypermedia approach with special ontological scaffolding to explore conceptual change and far knowledge transfer issues related to learning advanced scientific knowledge involving complex systems is also discussed.