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Diversity has historically played a critical role in design of combinatorial libraries, screening sets and corporate collections for lead discovery. Large library design dominated the field in the 1990s with methods ranging anywhere from purely arbitrary through property based reagent selection to product based approaches. In recent years, however, there has been a downward trend in library size. This was due to increased information about the desirable targets gleaned from the genomics revolution and to the ever growing availability of target protein structures from crystallography and homology modeling. Creation of libraries directed toward families of receptors such as GPCRs, kinases, nuclear hormone receptors, proteases, etc., replaced the generation of libraries based primarily on diversity while single target focused library design has remained an important objective. Concurrently, computing grids and cpu clusters have facilitated the development of structure based tools that screen hundreds of thousands of molecules. Smaller "smarter" combinatorial and focused parallel libraries replaced those early un-focused large libraries in the twenty-first century drug design paradigm. While diversity still plays a role in lead discovery, the focus of current library design methods has shifted to receptor based methods, scaffold hopping/bio-isostere searching, and a much needed emphasis on synthetic feasibility. Methods such as "privileged substructures based design" and pharmacophore based design still are important methods for parallel and small combinatorial library design. This chapter discusses some of the possible design methods and presents examples where they are available.