The wealth of information available from the solution of the human genome has dramatically altered the nature of combinatorial library design. While single-target-focused library design remains an important objective, creation of libraries directed toward families of receptors such as GPCRs, kinases, nuclear hormone receptors, and proteases, has replaced the generation of libraries based primarily on diversity. Although diversity-based design still plays a role for receptors with no known ligands, more knowledge-based approaches are required for target class design. This chapter discusses some of the possible design methods and presents examples where they are available.