ERBB receptors, including EGFR, HER2, HER3, and HER4, have been linked to human cancer pathogenesis for nearly three decades. The understanding of the biology underlying cancer dependence on aberrant ERBB receptor signaling has led to the identification of genetic alterations in these receptors and the development of mechanism-based therapies. This Perspective discusses the current paradigms of targeting ERBB receptors with cancer therapeutics, the mechanisms of action, and resistance to these drugs. Despite the progress, current strategies still have limitations, and future research is needed to overcome resistance and develop more effective treatments. The ERBB family members play a prominent role in the initiation and maintenance of solid tumors, leading to the development of specific ERBB inhibitors. HER2 and EGFR are particularly important in breast and lung cancers, respectively, and their overexpression or mutations are associated with poor outcomes. Somatic mutations in HER2 and EGFR have been identified in various cancers, and these mutations often confer resistance to targeted therapies. The downstream signaling pathways activated by ERBB receptors, such as PI3K/AKT and MEK/ERK, are crucial for cancer progression and resistance to inhibition. Intrinsic and acquired resistance mechanisms, including the maintenance of downstream signaling pathways and the activation of bypass pathways, are discussed. The development of combination therapies and the exploration of predictive biomarkers are also highlighted as potential strategies to overcome resistance.ERBB receptors, including EGFR, HER2, HER3, and HER4, have been linked to human cancer pathogenesis for nearly three decades. The understanding of the biology underlying cancer dependence on aberrant ERBB receptor signaling has led to the identification of genetic alterations in these receptors and the development of mechanism-based therapies. This Perspective discusses the current paradigms of targeting ERBB receptors with cancer therapeutics, the mechanisms of action, and resistance to these drugs. Despite the progress, current strategies still have limitations, and future research is needed to overcome resistance and develop more effective treatments. The ERBB family members play a prominent role in the initiation and maintenance of solid tumors, leading to the development of specific ERBB inhibitors. HER2 and EGFR are particularly important in breast and lung cancers, respectively, and their overexpression or mutations are associated with poor outcomes. Somatic mutations in HER2 and EGFR have been identified in various cancers, and these mutations often confer resistance to targeted therapies. The downstream signaling pathways activated by ERBB receptors, such as PI3K/AKT and MEK/ERK, are crucial for cancer progression and resistance to inhibition. Intrinsic and acquired resistance mechanisms, including the maintenance of downstream signaling pathways and the activation of bypass pathways, are discussed. The development of combination therapies and the exploration of predictive biomarkers are also highlighted as potential strategies to overcome resistance.