The combination of polymeric with biological materials, to create biohybrid macromolecules that merge the properties of both the natural and synthetic components, is a flourishing area in both life sciences and biotechnology. The click chemistry philosophy has recently provided a powerful tool in this direction, leading to a plethora of novel, tailor-made biomacromolecules with unprecedented structural characteristics and properties. The different synthetic strategies, using the alkyne-azide click cycloadditions to bioorthogonally achieve the coupling of synthetic polymers with nucleic acids, peptides, sugars, proteins or even viruses and cells is described. The review covers the latest developments in this very dynamic and rapidly expanding field.