The invention relates to systems and methods for tomographic imaging in diffuse media employing a fast reconstruction technique. A hybrid Fourier approach is presented that enables the fast tomographic reconstruction of large datasets. In certain embodiments, the invention features methods of in vivo fluorescence molecular tomographic (FMT) reconstruction of signals, reporters and/or agents (i.e., contrast agents or probes) in a diffusive medium (e.g., a mammalian subject). The method preserves the three-dimensional fluorophore distribution and quantitative nature of the FMT approach while substantially accelerating its computation speed, allowing FMT imaging of larger anatomies.