Solid-phase combinatorial synthesis using split-pool or direct divide methods allows large libraries of complex molecules to be generated. Encoding techniques used during synthesis allow the identities of the products to be determined readily. An overview of this process and its application to ligand discovery are presented, along with comparisons to alternative approaches. Libraries are classified depending upon their intended use as discovery libraries (for broad screening), targeted libraries (for structure-based screening) and optimization libraries (for activity improvement). Biological assays can be performed on the solid support that is used in synthesis, or in solution under in vitro or in vivo conditions, with readouts indicative of either receptor binding or biological activity. This approach has led to numerous examples of successful ligand discovery.