The ability to chemically modify complex proteins in a highly selective way is one of the major challenges in chemical biology. Although enzyme-mediated or recombinant techniques can be very powerful and direct ways to alter and probe protein structure and function, such methods are often limited to highly specific applications. True chemical (synthetic) methods offer the perspective of turning any protein structure into a versatile, custom-made biological tool, probe or even therapeutic protein conjugate. In this proposal, we aim to explore two highly promising and complementary synthetic strategies that –in the groups of the applicants –have very recently shown potential to achieve this ambitious goal. On the one hand, the masked reactivity of furan moieties will be used to aim for site-specific chemical modifications of proteins. On the other hand, a recently developed novel click chemistry platform will be explored for the purpose of highly selective protein modifications. We aim to demonstrate the possibilities of our chemical technology in the selective derivatisation of artificial antibodies or nanobodies, in covalent receptor fishing studies using modified peptide ligands, and in site-selective conjugations to natural or recombinant proteins, including those with easily-incorporable non-natural amino acids.