This chapter focuses on solid-phase (SP) combinatorial chemistry and libraries, and on their most recent applications in the drug discovery process. The first section provides a short history of combinatorial chemistry, and examines the most relevant trends which appeared recently. Among them, the use of combinatorial techniques in natural products’ research, and in the identification and the validation of novel pharmaceutical targets. The main section lists the most important SP libraries prepared since 2000, dividing the references in three categories: a set of publications reporting the SP assessment prior to SP library synthesis comes first, followed by the description of SP discrete libraries and SP pool libraries. The same partitioning is used in the last section, describing in details the accomplishments of four major laboratories active in drug discovery-driven SP combinatorial library synthesis.