Aviation security, mail inspection, medical diagnostics and many other industries all face the same challenge: to accurately identify the presence of a target material concealed within a cluttered surrounding environment. X-ray systems that combine transmission and diffraction measurements promise excellent detection performance with low false alarm rates; however, conventional approaches to combining these measurements typically under-utilize the available information and result in higher overall system resource costs. Here, we consider a fully integrated approach to hybrid X-ray transmission and diffraction systems and discuss simulation- and experimental-based investigations of the design and performance (both imaging and detection) of such systems. Based on this analysis, we describe a hybrid system capable of scanning boxes and/or luggage and report its ability to distinguish materials of interest to aviation security and pharmaceutical inspection.