Project Abstract The goal of the proposed work is to develop a novel dual-layer flat-panel detector (DLFPD) based on mature energy-integrating detector technology and translate it clinically for dual- energy spectral digital breast tomosynthesis (DE-DBT). This will improve the outcome of breast cancer screening, diagnosis and treatment monitoring. Our objectives are two folds: 1. Develop a DLFPD to allow rapid clinical translation of spectral breast imaging without patient motion artifact. 2. Develop spectral imaging techniques based on DLFPD and establish its clinical feasibility using patient studies. Our objectives will be accomplished through the following three specific aims: (1) Design, optimize and fabricate a prototype DLFPD for spectral breast imaging. Aim 1 will lead to the development and clinical translation of DLFPD that acquires two mammograms at different energies using a single exposure, allowing perfectly registered spectral images without artifacts due to patient motion. (2) Develop DLFPD based DE-DBT techniques using simulation methods. Aim 2 will lead to the development of spectral image processing techniques for DLFPD based systems with and without iodinated contrast agent. (3) Integrate the prototype DLFPD with a clinical DBT system and investigate DE-DBT performance through phantom and patient imaging studies. Aim 3 will translate the DLFPD and DE-DBT techniques developed in Aims 1 and 2 into clinical reality. The outcomes of the proposed work are: 1. Advancement in DLFPD hardware that permit rapid clinical translation; 2. Development of a variety of DLFPD based DE-DBT techniques, with and without iodinated contrast agent; 3. Clinical evaluation of the feasibility of DE-DBT for breast cancer detection.