Recent evidence demonstrating the importance of structural complexity in advancing compounds to the clinic points to the need for enhancing small molecule screening collections with sp3-rich compounds. The development of diversity-oriented synthesis (DOS) strategies for accessing libraries of sp3-rich compounds containing one or more stereogenic centers will be presented, including an overview of library synthesis efforts at H3 Biomedicine and the Broad Institute. The DOS libraries which have been created span a broad range of molecular frameworks, including macrocycles and medium-sized rings, as well as fused-, bridged- and spirocyclic- ring systems. Cheminformatic design principles and library analysis will be discussed as well as results of high-throughput screening against oncology targets.