Covalent chemical probes enable investigation of a desired fraction of the proteome. It is possible to adjust the selectivity of these probes, so they either react with a certain amino acid in all proteins, a class of proteins or only a single protein species. A combination of specific reactive groups with additional recognition elements can fine tune probes to hit the desired proteins, even in the presence of related family members. Using probes of lower or higher selectivity, screening experiments for inhibitor discovery and imaging experiments for localization studies can be performed, showing only a fraction of the power of covalent small molecule probes.