Purpose A system architecture has been developed for integration of intraoperative 3D imaging [viz., mobile C-arm cone-beamCT (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 A. Uneri Department of Computer Science, Johns Hopkins University, Traylor Building, Room #726, 720 Rutland Avenue, Baltimore, MD 21205-2109, USA e-mail: ali.uneri@jhu.edu S. Schafer · S. Nithiananthan Department of Biomedical Engineering, Johns Hopkins University, Traylor Building, Room #726, 720 Rutland Avenue, Baltimore, MD 21205-2109, USA e-mail: sebastian.schafer@jhu.edu S. Nithiananthan e-mail: sajendra@jhu.edu D. J. Mirota Department of Computer Science, Johns Hopkins University, 224 NEB, 3400 N. Charles Street, NE Baltimore, MD 21218, USA e-mail: dan@cs.jhu.edu 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 Y. Otake Department of Computer Science, Johns Hopkins University, 128 Hackerman Hall, 3400 N. Charles Street, NE Baltimore, MD 21218, USA e-mail: otake@jhu.edu R. H. Taylor Department of Computer Science, Johns Hopkins University, 127 Hackerman Hall, 3400 N. Charles Street, NE Baltimore, MD 21218, USA e-mail: rht@jhu.edu J. H. Siewerdsen Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA J. H. Siewerdsen (B) Department of Biomedical Engineering, Johns Hopkins University, Traylor Building, Room #718, 720 Rutland Avenue, Baltimore, MD 21205-2109, USA e-mail: jeff.siewerdsen@jhu.edu