PURPOSE: A system architecture has been developed for integration of intraoperative 3D imaging [viz., mobile C-arm cone-beam CT (CBCT)] with surgical navigation (e.g., trackers, endoscopy, and preoperative image and planning data). The goal of this paper is to describe the architecture and its handling of a broad variety of data sources in modular tool development for streamlined use of CBCT guidance in application-specific surgical scenarios. METHODS: The architecture builds on two proven open-source software packages, namely the cisst package (Johns Hopkins University, Baltimore, MD) and 3D Slicer (Brigham and Women's Hospital, Boston, MA), and combines data sources common to image-guided procedures with intraoperative 3D imaging. Integration at the software component level is achieved through language bindings to a scripting language (Python) and an object-oriented approach to abstract and simplify the use of devices with varying characteristics. The platform aims to minimize offline data processing and to expose quantitative tools that analyze and communicate factors of geometric precision online. Modular tools are defined to accomplish specific surgical tasks, demonstrated in three clinical scenarios (temporal bone, skull base, and spine surgery) that involve a progressively increased level of complexity in toolset requirements. RESULTS: The resulting architecture (referred to as "TREK") hosts a collection of modules developed according to application-specific surgical tasks, emphasizing streamlined integration with intraoperative CBCT. These include multi-modality image display; 3D-3D rigid and deformable registration to bring preoperative image and planning data to the most up-to-date CBCT; 3D-2D registration of planning and image data to real-time fluoroscopy; infrared, electromagnetic, and video-based trackers used individually or in hybrid arrangements; augmented overlay of image and planning data in endoscopic or in-room video; and real-time "virtual fluoroscopy" computed from GPU-accelerated digitally reconstructed radiographs (DRRs). Application in three preclinical scenarios (temporal bone, skull base, and spine surgery) demonstrates the utility of the modular, task-specific approach in progressively complex tasks. CONCLUSIONS: The design and development of a system architecture for image-guided surgery has been reported, demonstrating enhanced utilization of intraoperative CBCT in surgical applications with vastly different requirements. The system integrates C-arm CBCT with a broad variety of data sources in a modular fashion that streamlines the interface to application-specific tools, accommodates distinct workflow scenarios, and accelerates testing and translation of novel toolsets to clinical use. The modular architecture was shown to adapt to and satisfy the requirements of distinct surgical scenarios from a common code-base, leveraging software components arising from over a decade of effort within the imaging and computer-assisted interventions community.