The Hippo signaling pathway, originally identified in Drosophila melanogaster in 1995, plays a critical role in organ size control and tumor suppression by inhibiting cell proliferation and promoting apoptosis. Key components include MST1/2, LATS1/2, YAP, and TAZ. Dysregulated Hippo signaling is linked to tumorigenesis, epithelial-mesenchymal transition (EMT), oncogenic stemness, and drug resistance. Hippo signaling components are central to oncogenic adaptations, contributing to drug resistance in cancers like those driven by KRAS and EGFR mutations. The Hippo pathway's interaction with other oncogenic drivers, such as KRAS and EGFR, is crucial for developing combination therapies targeting aggressive tumors and drug resistance. YAP/TAZ activation is associated with cancer cell proliferation, migration, metastasis, and drug resistance. They drive the expression of cell cycle genes and are frequently amplified in cancers like head and neck and gynecologic cancers. YAP/TAZ also promotes EMT and stemness, enhancing tumor progression. TEADs, which interact with YAP/TAZ, are key transcriptional partners. TEADs regulate Hippo-YAP/TAZ signaling and are involved in oncogenic adaptations. Targeting TEADs has emerged as a promising therapeutic strategy, especially in cancers with YAP/TAZ amplification or mutations. Recent studies highlight the role of TEAD inhibitors in overcoming drug resistance, particularly in KRAS G12C-mutant cancers. Combination therapies targeting TEADs with KRAS inhibitors show promise in improving treatment outcomes. Additionally, YAP/TAZ-TEAD signaling is involved in EGFR-driven tumors, where combined inhibition of EGFR and YAP/TAZ-TEAD enhances therapeutic efficacy. The Hippo pathway's interaction with other signaling pathways, such as MAPK and Wnt, underscores its importance in cancer progression and drug resistance. Targeting the Hippo pathway, particularly YAP/TAZ-TEAD, offers a viable approach for combination therapies to overcome oncogenic adaptations and drug resistance. Ongoing research into TEAD inhibitors and their mechanisms of action is crucial for developing effective treatments for cancers driven by mutations in KRAS and EGFR. The development of small-molecule inhibitors targeting TEADs, along with combination strategies, represents a promising direction in cancer therapy.The Hippo signaling pathway, originally identified in Drosophila melanogaster in 1995, plays a critical role in organ size control and tumor suppression by inhibiting cell proliferation and promoting apoptosis. Key components include MST1/2, LATS1/2, YAP, and TAZ. Dysregulated Hippo signaling is linked to tumorigenesis, epithelial-mesenchymal transition (EMT), oncogenic stemness, and drug resistance. Hippo signaling components are central to oncogenic adaptations, contributing to drug resistance in cancers like those driven by KRAS and EGFR mutations. The Hippo pathway's interaction with other oncogenic drivers, such as KRAS and EGFR, is crucial for developing combination therapies targeting aggressive tumors and drug resistance. YAP/TAZ activation is associated with cancer cell proliferation, migration, metastasis, and drug resistance. They drive the expression of cell cycle genes and are frequently amplified in cancers like head and neck and gynecologic cancers. YAP/TAZ also promotes EMT and stemness, enhancing tumor progression. TEADs, which interact with YAP/TAZ, are key transcriptional partners. TEADs regulate Hippo-YAP/TAZ signaling and are involved in oncogenic adaptations. Targeting TEADs has emerged as a promising therapeutic strategy, especially in cancers with YAP/TAZ amplification or mutations. Recent studies highlight the role of TEAD inhibitors in overcoming drug resistance, particularly in KRAS G12C-mutant cancers. Combination therapies targeting TEADs with KRAS inhibitors show promise in improving treatment outcomes. Additionally, YAP/TAZ-TEAD signaling is involved in EGFR-driven tumors, where combined inhibition of EGFR and YAP/TAZ-TEAD enhances therapeutic efficacy. The Hippo pathway's interaction with other signaling pathways, such as MAPK and Wnt, underscores its importance in cancer progression and drug resistance. Targeting the Hippo pathway, particularly YAP/TAZ-TEAD, offers a viable approach for combination therapies to overcome oncogenic adaptations and drug resistance. Ongoing research into TEAD inhibitors and their mechanisms of action is crucial for developing effective treatments for cancers driven by mutations in KRAS and EGFR. The development of small-molecule inhibitors targeting TEADs, along with combination strategies, represents a promising direction in cancer therapy.