Abstract: D-Flow is a software system designed for the development of interactive and immersive virtual reality applications, for the purpose of clinical research and rehabilitation. Key concept of the D-Flow software system is that the subject is regarded as an integral part of a real-time feedback loop, in which multi-sensory input devices measure the behavior of the subject, while output devices return motor-sensory, visual and auditory feedback to the subject. The D-Flow software system allows an operator to define feedback strategies through a flexible and extensible application development framework, based on visual programming. We describe the requirements, architecture and design considerations of the D-Flow software system, as well as a number of applications that have been developed using D-Flow, both for clinical research and rehabilitation.