Combinatorial libraries composed of ten to hundreds of millions of compounds have attained widespread acceptance over the past four years as broadly applicable research and drug discovery tools. Case studies involving either antibody- or receptor-based opioid assays have demonstrated the feasibility and practicality of library approaches for the study and identification of new opioid ligands. The two most commonly used assays are ELISA, in conjunction with a monoclonal antibody raised against β-endorphin (mAb 3E7), and a radioreceptor binding assay specific for the μ-opioid receptor. These two assays provide a framework for the comparison of a number of different combinatorial library approaches. In this review, combinatorial approaches which have been tested in either of these assays are presented, and the compounds identified from these libraries are compared.