Chemical probes are key components of thebioimaging toolbox, as they label biomolecules in cells andtissues. The new challenge in bioimaging is to design chemicalprobes for three-dimensional (3D) tissue imaging. In thiswork, we discovered that light scattering of metal nanoparticlescan provide 3D imaging contrast in intact and transparenttissues. The nanoparticles can act as a template for thechemical growth of a metal layer to further enhance thescattering signal. The use of chemically grown nanoparticles inwhole tissues can amplify the scattering to produce a 1.4million-fold greater photon yield than obtained using commonfluorophores. These probes are non-photobleaching and canbe used alongside fluorophores without interference. Wedemonstrated three distinct biomedical applications: (a) molecular imaging of blood vessels, (b) tracking of nanodrug carriers in tumors, and (c) mapping of lesions and immune cells in a multiple sclerosis mouse model. Our strategy establishes a distinct yet complementary set of imaging probes for understanding disease mechanisms in three dimensions.