Schematic shows strategies, which are highlighted in this Review, to overcome chemotype-specific resistance to inhibitors. The activity of resistance-conferring alleles (dark gray, center) can be blocked by inhibitors with distinct binding modes, allosteric inhibitors, covalent inhibitors, or bivalent compounds. Resistance-conferring alleles can also be targeted for degradation by the proteasome using PROTACs (red ligand with a green star, see text for details).