Based on investigations on the biochemistry of the protease-inhibitor interaction and on the analysis of detailed inhibition kinetics, we are designing and synthesizing tailored inhibitors for therapeutically relevant proteases, including human cysteine cathepsins, involved in tumor progression, and the main protease of SARS-CoV-2, a cysteine protease. We equipped such synthetic inhibitors with reporter groups to assemble activity-based probes as valuable tool compounds to study target enzymes in a pathophysiological context. Proteolysis targeting chimeras (PROTACs) are bifunctional small molecules, which simultaneously bind a target protein and an E3 ubiquitin ligase. We are developing PROTACs, e.g. for the self-directed ubiquitination and degradation of cereblon or the degradation of cyclin-dependent kinases, thus significantly contributing to this pioneering new modality in drug discovery.