A novel kind of monodisperse core-shell silica nanosphere composed of a fluorescent solid core and a mesoporous shell has been successfully fabricated. These nanospheres exhibit multifluorescent signals under a single-wavelength excitation as a result of the solid silica core that is doped with three kinds of dyes and that can produce effective fluorescence resonance energy transfer. The fluorescent signal of a single nanosphere is about 700 times brighter than its constituent fluorophores. X-ray diffraction, transmission electron microscopy, and N(2) adsorption-desorption isotherms reveal that these nanospheres possess abundant mesopores in the shell. Combining the advantages of extremely bright multifluorescent signals excited with a single wavelength and an abundant mesoporous system, this core-shell silica nanosphere is designed for the simultaneous monitoring of fluorescence of in vivo multiple-target drug transport. Experiments on drug loading and release in addition to studies on cell uptake reveal that these nanospheres not only show good drug storage and sustained release capacity but also demonstrate biocompatibility and mutlifluorescent labeling capacity for biological systems.