Cone-beam computed tomography (CBCT) presents a highly promising and challenging advanced application of flat-panel detectors (FPDs). The great advantage of this adaptable technology is in the potential for sub-mm 3D spatial resolution in combination with soft-tissue detectability. While the former is achieved naturally by CBCT systems incorporating modern FPD designs (e.g., 200 - 400 um pixel pitch), the latter presents a significant challenge due to limitations in FPD dynamic range, large field of view, and elevated levels of x-ray scatter in typical CBCT configurations. We are investigating a two-pronged strategy to maximizing soft-tissue detectability in CBCT: 1) front-end solutions, including novel beam modulation designs (viz., spatially varying compensators) that alleviate detector dynamic range requirements, reduce x-ray scatter, and better distribute imaging dose in a manner suited to soft-tissue visualization throughout the field of view; and 2) back-end solutions, including implementation of an advanced FPD design (Varian PaxScan 4030CB) that features dual-gain and dynamic gain switching that effectively extends detector dynamic range to 18 bits. These strategies are explored quantitatively on CBCT imaging platforms developed in our laboratory, including a dedicated CBCT bench and a mobile isocentric C-arm (Siemens PowerMobil). Pre-clinical evaluation of improved soft-tissue visibility was carried out in phantom and patient imaging with the C-arm device. Incorporation of these strategies begin to reveal the full potential of CBCT for soft-tissue visualization, an essential step in realizing broad utility of this adaptable technology for diagnostic and image-guided procedures.