The Post-genomic era calls for a deep understanding of protein structure and function. The elucidation of protein structures, localization, post-translation modifications, and protein-macromolecule interactions are important to establish their role in the biology of the cell. To establish their role and investigate the protein functions requires the integration of various complementary disciplines. Among all disciplines, chemistry is central in establishing new effective ways to manipulate a biological entity to understand cellular processes with molecular precision. For studying, analyzing and manipulating a macromolecule, the site-specific incorporation of reporter molecules, by virtue of ligation reactions, is a key factor. The BioChemLig research project presented herein describes novel approaches for the discovery of new bio-compatible and chemo-specific ligation reactions. The aim of this project is to develop new ligation processes with high efficiency, large scope of application, high chemoselectivity and high rates. Through a well established network, with demonstrated success (IBAAC Project: FP6-505020), we propose to focus our efforts in a highly combined and integrated training research action conducting research and using: unusual organic chemical functionalities for ligation, environmentally benign “on water” ligation reactions, specific 18F radiolabelled reagents, dendrimers conjugation methodologies, high-throughput screening for bond forming reactions, bio-chemo informatics platform for theoretical investigations, artificial metalo-enzymes for template-directed ligation, templated ligation reactions and HTS. This high quality integrated research should ultimately allow scientists to dissect cellular processes with molecular precision, speed up preparation of library of bioconjugates and deliver innovatives approaches to chemical biology.