Previous research has indicated that use of guidance systems during endoscopy can improve the performance and decrease the skill variation of physicians. Current guidance systems, however, rely on computationally intensive registration techniques or costly and error-prone electromagnetic (E/M) registration techniques, neither of which fit seamlessly into the clinical workflow. We have previously proposed a real-time image-based registration technique that addresses both of these problems. We now propose a system-level approach that incorporates this technique into a complete paradigm for real-time image-based guidance in order to provide a physician with continuously-updated navigational and guidance information. At the core of the system is a novel strategy for guidance of endoscopy. Additional elements such as global surface rendering, local cross-sectional views, and pertinent distances are also incorporated into the system to provide additional utility to the physician. Phantom results were generated using bronchoscopy performed on a rapid prototype model of a human tracheobronchial airway tree. The system has also been tested in ongoing live human tests. Thus far, ten such tests, focused on bronchoscopic intervention of pulmonary patients, have been run successfully.