The term of combinatorial chemistry has come to embrace all types of small-molecule library strategies. In both academic and industrial settings, the development of many combinatorial techniques has been driven by a desire to generate diverse libraries of molecules. Recently, chemical approaches have been reported that range from alternative library design concepts to new synthetic procedures that allow for selective product formation in extremely short reaction times. Concurrently, biological techniques have made great strides by adapting naturally occurring strategies for library preparation and screening. With proper understanding of library design, combinatorial endeavors and molecular libraries will continue to impact on the development of the next generation of tools for modern medicine.