Monoclonal antibody (mAb)-based therapies have been a major advance in oncology patient care, even though they represent a significant healthcare cost. Biosimilars, launched in Europe in 2004 are an economically attractive alternative to expensive originator biological drugs. They also increase the competitiveness of pharmaceutical development. This article focuses on the case of Erbitux® (cetuximab). This anti-EGFR (Epidermal Growth Factor Receptor) monoclonal antibody is indicated for metastatic colorectal cancer (2004) and squamous cell carcinoma of the head and neck (2006). However, despite the expiration of the patent in Europe in 2014 and estimated annual sales of 1.681 million US dollars in 2022, Erbitux® has not yet faced any approved biosimilar challenges in the United States or in Europe. Here, we outline the unique structural complexity of this antibody highlighted by advanced orthogonal analytical characterization strategies resulting in risks to demonstrate biosimilarity, which may explain the lack of Erbitux® biosimilars in the European and US markets to date. The development of Erbitux® biobetters are also discussed as alternative strategies to biosimilars. These biologics offer expected additional safety and potency benefits over the reference product but require a full pharmaceutical and clinical development as for New Molecular Entities.