In vivo imaging of small animal models will play an increasingly important role in cancer research, as new imaging systems that employ non-invasive protocols and offer high-resolution capability become available. A flat-panel volumetric computed tomograph (fpvCT) was evaluated to determine if minimally invasive protocols can be used to provide the spatial resolution required for lung imaging in small animals. The detection of small pulmonary nodules in a Lewis carcinoma model was investigated, and fpvCT was compared with a multislice computed tomograph (MSCT). Five C57/BL6 mice with Lewis lung carcinoma were monitored with both modalities over two weeks. Sensitivity of the systems was measured by comparing the results with histology, and the incidence of first visualization of the tumors in the two systems was determined. Compared to MSCT, fpvCT proved its superior sensitivity in detection of lung nodules. Due to its isotropic resolution and a significant reduction of partial volume effects, early detection and reasonable determination of growth in very small tumors was only possible with fpvCT. fpvCT is a high-resolution imaging system that proved its ability to perform in vivo monitoring of a pulmonary lung tumor model in mice. This permits longitudinal investigations in small animals for cancer research.