Project Summary Although the precise definition of “chemical biology” can be a subject for lively discussion, it is universally understood to entail the use of small molecules and peptides for greater understanding of biology. Depending on the goals of its specific practitioners, the specific compounds discovered in the context of a chemical biology program are most often pharmacological tools for in vitro or in vivo elucidation of particular pathways. In some cases, however, the development of such “probes” constitutes the first step toward drug discovery by providing lead compounds for preclinical study. In either case, the success of a given chemical biology project requires the identification of suitable molecules for study, the optimization of desired properties at the expense of undesired properties, and the construction of custom-made probes for additional biological evaluation. Since it is rare that an ideal probe molecule is sitting in a screening collection just waiting to be discovered, all of the above activities rely on synthetic medicinal chemistry to optimize initial hits and ultimately provide the molecule around which a chemical biology program will be based. The Core D, Synthetic Chemical Biology, will enable researchers to understand and combat infectious disease by providing design and synthesis of peptides and small molecules that are chemically targeted to the specific biological needs.