There is a growing need for biocompatible click reactions in order to prepare multifunctional conjugates, which are valuable molecules for innovative biomedical applications. In this context, we review the recent advances in the implementation of oxime ligation for the synthesis of multivalent or multicomponent systems. The value of these products is emphasized by their use in cell targeting, imaging, synthetic vaccines, and surface modifications. Piecing the puzzle together: Chemoselective and biocompatible click reactions are important tools for the preparation of complex bioconjugates. Oxime ligation has recently emerged as a powerful click-type methodology (see scheme) for the effective engineering of multifunctional constructs, since it takes place in aqueous systems under mild acidic conditions, is compatible with most of the biomolecule functionalities, and generates only water as a side-product.