Hybrid nanoparticles, composed of both inorganic and organic components, have been exploited as promising platforms for cancer imaging and therapy. This class of nanoparticles can not only retain the beneficial features of both inorganic and organic materials, but also allow systematic fine-tuning of their properties through the judicious combination of functional components. This chapter summarizes recent advances in the design and synthesis of hybrid nanomaterials, with particular emphasis on two main categories of hybrid nanoparticles: Nanoscale metal-organic frameworks (also known as nanoscale coordination polymers) and polysilsesquioxane nanoparticles. Preliminary applications of these hybrid nanoparticles in cancer imaging and therapy are described.