Emerging strategies targeting site-specific protein modifications allow for unprecedented selectivity, fast kinetics and mild reaction conditions with high yield. These advances open exciting novel possibilities for the effective bioorthogonal decoration of biomaterials with therapeutic proteins. Site-specificity is particularly important to the therapeutics' end and translated by targeting specific functional groups or introducing new functional groups into the therapeutic at predefined positions. Biomimetic strategies are designed for modification of therapeutics emulating enzymatic strategies found in Nature. These strategies are suitable for a diverse range of applications – not only for protein-polymer conjugation, particle decoration and surface immobilization, but also for the decoration of complex biomaterials and the synthesis of bioresponsive drug delivery systems. This article reviews latest chemical and enzymatic strategies for the biorthogonal decoration of biomaterials with therapeutic proteins and inter-positioned linker structures. Finally, the numerous reports at the interface of biomaterials, linkers, and therapeutic protein decoration are integrated into practical advice for design considerations intended to support the selection of productive ligation strategies.