New opportunities to advance small-molecule kinase ligands that downregulate their cognate target binding proteins are discussed. Rationally designed heterobifunctional kinase degraders are compared with ATP site ligands that were serendipitously found to cause kinase downregulation. These approaches could be particularly useful in the treatment of cancers since many kinases are known to remodel pro-oncogenic protein-protein interactions, which could be destroyed by small-molecule-mediated kinase depletion.