A set of skills and knowledge learned from students’ experiences with well-structured problems, which have often been employed in typical college classrooms, are not enough for them to solve real-world problems, which are often characterized as uncertain, dynamic, complex, vague, urgent, time-pressed, and ill-structured. Although the goal of higher education is to help students be successful professionals who are able to deal with real-world problems and to make subtle and responsible judgments in their everyday profession, instructors or trainers are often challenged to teach these kinds of skills, whether in the existing classroom, e-learning, and/or blended settings. Can case-based interactive e-learning systems overcome this kind of challenge? This presentation will answer the question by proposing a framework integrating three types of knowledge that helps to diagnose the limitations of existing learning environments, presenting instructional design models and development techniques for case-based e-learning systems, and demonstrating cases which illustrate how case-based interactive e-learning systems help to facilitate real-world problem solving skills in college classrooms such as anesthesiology, orthopedic surgery, and elementary classroom management.