Immunogenicity assessment of therapeutic proteins is routinely performed through various techniques during the drug development process: (i) in silico to design the least immunogenic protein possible, (ii) in vitro using mainly classic 2D assays with PBMC-derived cells or immune cell lines to follow protein uptake, immune cell maturation and pro-inflammatory cytokines released, (iii) in vitro using 3D models of the human immune lymphatic system or full-thickness skin, (iv) and finally in vivo with preclinical and clinical studies. This review focuses primarily on the immunogenicity assessment of therapeutic proteins injected subcutaneously and new in vitro models that may be used as specific models of this tissue.