ABSTRACT Dedicated breast CT can eliminate tissue superposition that contributes to false-positives and false- negatives, and alleviates the need for physical compression of the breast. It provides for 3D images at near-isotropic spatial resolution that allows for viewing the breast in any orientation without the need for repeat acquisitions. It is an emerging technology, with only about five teams conducting research, worldwide. In order to develop, evaluate, accelerate its clinical translation, and to facilitate the widespread clinical adaptation of this technology, we are collaborating with GE Global Research to develop an upright patient positioning geometry with advanced technological capabilities designed to eventually allow for breast cancer screening, in addition to diagnostic imaging. The technological advanced proposed include an x-ray imaging detector with reduced system (electronic) noise, data readout rates improved by a factor of at least 2, and improved spatial sampling (pixel pitch) by a factor of 2 or more; a short-scan acquisition trajectory with angular range not exceeding 270-degrees that will improve patient positioning; and, the use of model-based iterative reconstruction techniques. All these technological advances are focused on improving posterior coverage, reducing the radiation dose to the breast so that it is similar to a standard 2- view mammography exam, and improving the visualization of microcalcifications; all with an aim of making it suitable for breast cancer screening in the future. Importantly, the upright geometry allows for rapid clinical adaptation as it allows for easy replacement of mammography and digital breast tomosynthesis systems, even in small mammography rooms, and addresses the patient discomfort observed with the prone breast CT. The research is broadly organized in two phases. In the first phase, all design factors and operational parameters will be verified through physics-based numerical simulations and empirical studies using the bench-top prototype system. In the second phase, we will conduct a clinical feasibility study that will recruit subjects from two cohorts: BIRADS 4/5, and screening population, to determine if the advanced technological approach using the upright, low-dose, high-resolution dedicated breast CT system improves the diagnostic accuracy compared to digital breast tomosynthesis. To our knowledge, this will be first study to directly compare digital breast tomosynthesis with dedicated breast CT. Thus, the proposed research will develop an innovative design concept for unprecedented impact in breast cancer imaging that will enable breast imaging without physical compression and at radiation dose similar to mammography. To our knowledge a compression-free breast CT system incorporating the aforementioned features does not exist.