<p>Targeted small molecule inhibitors have revolutionized oncology. With their help, deadly cancer entities like chronic myeloid leukemia can be transformed into controlled chronic diseases. Conventional inhibitors bind competitively to the active catalytic site of an enzyme, often an oncogenic hyperactivated kinase. However, despite the successful development and introduction of a&#xa0;large number of small molecule inhibitors in recent years, there are increasing challenges. The lack of deep binding pockets, high structural homology of the active sites of many oncoprotein families, and high cellular concentrations of competitive binding partners such as ATP render the design of highly selective potent inhibitors difficult. Therefore, no targeted drugs are yet available for the majority of the signaling molecules deregulated in tumors. The side effect profile and toxicity are also relevant problems, and resistance development due to point mutations is frequent. Allosteric inhibition is therefore a&#xa0;clever alternative. Allosteric inhibitors bind highly selectively to a&#xa0;regulatory site of the target oncoprotein, away from the active catalytic center, and enable targeted inhibition of oncoprotein classes that were previously considered inaccessible or of enzymes that have already developed resistance through mutation at the active center. Herein, the concept of allosteric inhibition is illustrated by the mechanism of action, clinical development status, and future potential of two new drug classes for inhibition of the BCR::ABL1 kinase and the oncogenic tyrosine phosphatase PTPN11/SHP2.</p>