Volume-of-interest (VOI) imaging is a strategy in computed tomography (CT) that restricts x-ray fluence to particular anatomical targets via dynamic beam modulation. This permits dose reduction while retaining image quality within the VOI. VOI-CT implementation has been challenged, in part, by a lack of hardware solutions for tailoring the incident fluence to the patient and anatomical site, as well as difficulties involving interior tomography reconstruction of truncated projection data. We propose a general VOI-CT imaging framework using multiple aperture devices (MADs), an emerging beam filtration scheme based on two binary x-ray filters. Location of the VOI is prescribed using two scout views at anterior–posterior (AP) and lateral perspectives. Based on a calibration of achievable fluence field patterns, MAD motion trajectories were designed using an optimization objective that seeks to maximize the relative fluence in the VOI subject to minimum fluence constraints. A modified penalized-likelihood method is developed for reconstruction of heavily truncated data using the full-field scout views to help solve the interior tomography problem. Physical experiments were conducted to show the feasibility of noncentered and elliptical VOI in two applications—spine and lung imaging. Improved dose utilization and retained image quality are validated with respect to standard full-field protocols. We observe that the contrast-to-noise ratio (CNR) is 40% higher compared with low-dose full-field scans at the same dose. The total dose reduction is 50% for equivalent image quality (CNR) within the VOI.