This Funding Opportunity Announcement (FOA) intends to support investigators who have interest and capability to join efforts for the discovery of in vivo chemical probes. It is expected that applicants will have in hand the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds. Through this FOA, NIH wishes to stimulate research in 1) discovery and development of novel, small molecules for their potential use in studying disease treatment relevant to the missions of the participating NIH Institutes, and 2) discovery and/or validation of novel, biological targets that will inform studies of disease mechanisms. Emphasis will be placed on assays that provide new insight into important disease targets and processes..