Femoral shaft fractures are commonly encountered in orthopaedics and are typically treated using intramedullary (IM) nailing under fluoroscopic guidance. Inaccuracies in the location of the entry point of the nail and the alignment of the reduced fracture are not uncommon during this procedure. This can greatly increase the risk of iatrogenic fractures, malunions and, potentially, secondary degenerative joint disease. Fluoroscopy-based computer-assisted navigation workflows have been developed but are, as yet, not widely used. As such, there is a need to investigate the performance of these systems as well as the possibility of using newer imaging methods to enhance the reduction accuracy. This body of work investigated the impact of off-angle fluoroscopic images on the accuracy and precision of the selection of the entry points used in IM nailing and found that, while images were considered to be clinically acceptable, they resulted in large deviations in the selection of the entry point. Although higher precision was achieved with navigation, it did not improve the accuracy. This work extended the investigation of off-angle images by investigating the impact of the variation in the landmarks used by current navigation methods on quantification of femoral anteversion. The observed landmark variations were propagated through the calculation of femoral anteversion and yielded errors exceeding current clinical tolerances. As an alternative to fluoroscopy, this work developed two, semi-automated algorithms to quantify femoral shaft fracture alignment in six degrees of freedom (6DOF) based on a single, intraoperative cone-beam CT scan. Both algorithms were able to accurately quantify malalignment in all 6DOF with high repeatability and limited user interaction over a range of complex femoral shaft fractures, even in cases with severe comminution. The time requirements for the utilization of these algorithms were reasonable with respect to the time required for current, fluoroscopy-based navigation. Therefore, both of these algorithms would provide an efficient, robust and accurate alternative for the quantification of malalignment in 6DOF. Such an accurate and robust quantification of malalignment, when paired with the high precision tracking in current navigation systems, may enable the improvement of reduction accuracy in the treatment of complex femoral shaft fractures.