This paper focuses on theory and research issues associated with the use of hypermedia technologies in education. It is proposed that viewing hypermedia technologies as an enabling infrastructure for tools to support learning--in particular learning in problem-based pedagogical environments involving cases--has particular promise. After considering research issues with problem-based learning related to knowledge transfer and conceptual change, a design framework is discussed for a hypermedia system with scaffolding features intended to support and enhance problem-based learning with cases. Preliminary results are reported of research involving a new version of this hypermedia design approach with special ontological scaffolding to explore conceptual change and far knowledge transfer issues related to learning advanced scientific knowledge involving complex systems as well as the use of the system in a graduate seminar class. Overall, it is hoped that this program of research will stimulate further work on learning and cognitive sciences theoretical and research issues, on the characteristics of design features for robust and educationally powerful hypermedia systems, on ways that hypermedia systems might be used to support innovative pedagogical approaches being used in the schools, and on how particular designs for learning technologies might foster learning of conceptually difficult knowledge and skills that are increasingly necessary in the 21st century.