PROJECT SUMMARY/ABSTRACT Combinatorial library methods not only offer great potential for facilitating the drug discovery process but also provide powerful tools for basic research in various disciplines. These methods enable investigators to generate large number of chemical compounds that can be used as valuable sources for the discovery of drug leads, molecular imaging agents, and capturing agents for molecular markers. In the past five years, the Combinatorial Chemistry Shared Resource (CCSR) has been assisting many cancer center investigators in the application of combinatorial chemistry to their research. These efforts have resulted in the submission and funding of several extramural grants, peer-reviewed publications. The CCSR provides high-number, low-cost library screening for novel compounds using one-bead-one-compound and one-bead-2-compounds methods, and a variety of on-bead and solution-phase functional assays. To expand the scope of the chemistry services provided by the CCSR, we have now added two new technology platforms that are useful to many cancer center members. The first technology is the use of amphiphilic telodendrimers to nanoformulate hydrophobic drugs for in vivo applications. The second technology is the development of Genetically Encoded Small Illuminants (GESIs) as novel reporters for cellular imaging of protein functions.