The application of high-performance flat-panel detectors (FPDs) to dual-energy (DE) imaging offers the potential for dramatically improved detection and characterization of subtle lesions through reduction of "anatomical noise," with applications ranging from thoracic imaging to image-guided interventions. In this work, we investigate DE imaging performance from first principles of image science to preclinical implementation, including: 1.) generalized task-based formulation of NEQ and detectability as a guide to system optimization; 2.) measurements of imaging performance on a DE imaging benchtop; and 3.) a preclinical system developed in our laboratory for cardiac-gated DE chest imaging in a research cohort of 160 patients. Theoretical and benchtop studies directly guide clinical implementation, including the advantages of double-shot versus single-shot DE imaging, the value of differential added filtration between low- and high-kVp projections, and optimal selection of kVp pairs, filtration, and dose allocation. Evaluation of task-based NEQ indicates that the detectabiliry of subtle lung nodules in double-shot DE imaging can exceed that of single-shot DE imaging by a factor of 4 or greater. Filter materials are investigated that not only harden the high-kVp beam (e.g., Cu or Ag) but also soften the low-kVp beam (e.g., Ce or Gd), leading to significantly increased contrast in DE images. A preclinical imaging system suitable for human studies has been constructed based upon insights gained from these theoretical and experimental studies. An important component of the system is a simple and robust means of cardiacgated DE image acquisition, implemented here using a fingertip pulse oximeter. Timing schemes that provide cardiacgated image acquisition on the same or successive heartbeats is described. Preclinical DE images to be acquired under research protocol will afford valuable testing of optimal deployment, facilitate the development of DE CAD, and support comparison of DE diagnostic imaging performance to low-dose CT and radiography.