The article reviews the role of the Hippo signaling pathway in cancer and drug resistance. Initially identified in *Drosophila melanogaster*, the Hippo pathway plays a crucial role in organ size control and tumor suppression by regulating proliferation and apoptosis. In mammals, the pathway involves MST1/2, LATS1/2, YAP, and TAZ, which are key components. Misregulation of this pathway is linked to various cancers, including glioma, breast, liver, lung, prostate, colorectal, and gastric cancers. The activation of YAP/TAZ, particularly through overexpression or loss of negative regulators, drives cancer cell proliferation, migration, and drug resistance. The article highlights the cross-talk between Hippo signaling and oncogenic drivers such as KRAS and EGFR, which contribute to tumor progression and drug resistance. Targeting the Hippo pathway, particularly through TEAD inhibitors, is proposed as a therapeutic strategy to overcome drug resistance and improve treatment outcomes. The review also discusses the potential of combination therapies, such as combining TEAD inhibitors with KRAS or EGFR inhibitors, to enhance the efficacy of targeted therapies and address the complexity of co-mutations in mutant cancers.The article reviews the role of the Hippo signaling pathway in cancer and drug resistance. Initially identified in *Drosophila melanogaster*, the Hippo pathway plays a crucial role in organ size control and tumor suppression by regulating proliferation and apoptosis. In mammals, the pathway involves MST1/2, LATS1/2, YAP, and TAZ, which are key components. Misregulation of this pathway is linked to various cancers, including glioma, breast, liver, lung, prostate, colorectal, and gastric cancers. The activation of YAP/TAZ, particularly through overexpression or loss of negative regulators, drives cancer cell proliferation, migration, and drug resistance. The article highlights the cross-talk between Hippo signaling and oncogenic drivers such as KRAS and EGFR, which contribute to tumor progression and drug resistance. Targeting the Hippo pathway, particularly through TEAD inhibitors, is proposed as a therapeutic strategy to overcome drug resistance and improve treatment outcomes. The review also discusses the potential of combination therapies, such as combining TEAD inhibitors with KRAS or EGFR inhibitors, to enhance the efficacy of targeted therapies and address the complexity of co-mutations in mutant cancers.