Diversity-oriented synthesis (DOS) is an important field involving the synthesis of libraries of diverse small molecules for applications including biological screening. The last decade has witnessed major progress in the field, with continued emphasis on structural and functional diversity for DOS library construction, leading to recent successes of biologically active molecules obtained from DOS compound collections. In the original paradigm for DOS, compound and library design were often based on the incorporation of functional, skeletal, and stereochemical diversity elements. An emerging theme in the area involves the development of novel reaction methodologies as a means to access or discover new “chemotypes”, advancing alongside the technology that enables progress in this area. In this way, organic chemists are empowered by the paradigm of “chemical diversity as a function of novel chemical reactions”, exploring a diverse repertoire of approaches to achieve their goals.