Unwanted immunogenicity is a significant issue affecting most biotherapeutic products, including subsequent entry biological (SEB) medicines. Such immunogenicity can be associated with adverse reactions and can cause impaired clinical responses to the biotherapeutic. This feature article provides an overview of the challenges facing the biotechnology industry with regard to the prediction and assessment of immunogenicity of SEBs and, in particular, biosimilar products. In addition, the available guidance on assessing the immunogenicity of biotherapeutic products is discussed.