The ERBB family of receptor tyrosine kinases plays a crucial role in cancer biology, particularly in tumorigenesis and the development of targeted therapies. The evolution and functional diversification of the ERBB family, which includes EGFR, HER2, HER3, and HER4, occurred through gene duplication events in ancient vertebrates. The importance of ERBB receptors in cancer is highlighted by their frequent genetic alterations, which include mutations, amplifications, and gene fusions. Despite advancements in targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, challenges remain due to the emergence of drug resistance mechanisms. This chapter explores the difficulties these resistance mechanisms pose and highlights the ongoing research into novel therapeutic strategies. Recent developments, such as bispecific antibodies and antibody-drug conjugates, promise to overcome resistance and improve patient outcomes in ERBB-driven cancers.