This first small-animal up-conversion imager (SAUCI) was developed and used for in-vivo imaging of up-converting nanoparticles (UCNs.) Unlike traditional fluorophores, UCNs absorb multiple lower-energy photons and emit a single higher-energy photon. This unique physical process makes it possible to image deeper into tissue with lower background signals. In vivo imaging of particle accumulation in the liver was demonstrated following intravenous injection of particles.