The central objective of this project is to find conceptually new ways to enter into cells, thus addressing an important challenge in current chemical biology. Complementary tools have been developed at the NCCR Chemical Biology which use new uptake pathways and can deliver otherwise problematic substrates. Current interest focuses on cellular uptake mediated by CPDs (cell-penetrating poly(disulfide)s) and COCs (cyclic oligochalcogenides). Extreme sulfur and selenium chemistry is explored to maximize speed and selectivity of dynamic covalent chalcogenide exchange chemistry on the way into cells. A better understanding the mode of action of these unorthodox transport systems is expected from conductance experiments in black lipid membranes. Newly introduced systems will be made available first to substrates and topics of interest in the NCCR community (protein-covered quantum dots, oligonucleotide delivery without charge neutralization, peptide nucleic acids, bicyclic peptides, antibodies, nanobodies, and so on). To bring the new tools and the diverse substrates together, we currently focus on bioorthogonal ligation, traceless delivery and non-covalent multifunctional interfacers.