The therapeutic use of monoclonal antibodies is growing exponentially. Our knowledge on antibody structure, in particular that of IgG1, largely used in the clinic, has progressed remarkably. However, some formidable challenges still remain to be confronted, among which the increase of a yet-limited antibody efficacy, the lowering of the frequency of serious clinical adverse events, and the establishment of pre-clinical models that can be reliably extrapolated to humans represent major goals. The selection of relevant target antigens with regard to the pathology to be treated and to the expected effects of the antibody used is also a critical parameter. Facing these challenges, the amazing molecular plasticity of antibodies, as well as new antibody engineering approaches based on the most recent insights on the structure and biology of antibodies and their targets represent areas of research that will make monoclonal antibodies remarkable drugs for human health in a near future.