Nanoparticles have been extensively investigated in drug-delivery systems. Especially, the effectiveness of the surface-functionalized nanoparticles, which consist of copolymers with functional molecules, is well demonstrated. This chapter describes the complete technique for the preparation of surface-functionalized nanoparticles. Tetracycline with an affinity to bone was chosen as a model material for surface functionalization. There are two steps for the preparation of tetracycline-modified nanoparticles. The first step is the conjugation of poly(D ,L -lactide-coglycolic acid) with tetracycline via carbodiimide chemistry and is the most often employed. Three kinds of techniques—the emulsification-diffusion method, nanoprecipitation, and the dialysis method—are used for nanoparticle formation of the resulting copolymer. Prepared nanoparticles having a size <200 nm and a hydrophilic surface layer can be applied for bone-specific drug delivery.