The common approach in fluorescence molecular tomography (FMT) assumes homogeneous distributions of the optical properties and normally results in reconstructions of low sensitivity. A natural enhancement is to incorporate diffuse optical tomography (DOT) to FMT. However, the traditional voxel-based DOT has been a severely ill-posed inverse problem and cannot retrieve the optical property distributions accurately. We present a structural-prior-based DOT method to effectively acquire the heterogeneous optical background with the aid of some imperfect structural priors from x-ray computed tomography and/or magnetic resonance imaging anatomical imaging modalities, and quantitatively compare its hard- and soft-prior schemes for achieving an improved recovery of the fluorescence distribution. Numerical simulations are conducted on a region-labeled three-dimensional (3D) digital mouse model to investigate the performance of this method. Physical experiments on a cylindrical phantom are also conducted to assess this methodology. Our simulated and experimental reconstruction results indicate that the structural-prior-based DOT guided FMT approach can significantly improve the sensitivity of FMT reconstruction, as well as its imaging resolution and quantitative accuracy.