Hydrogels are water swollen polymeric networks, capable of absorbing large amounts of water or biological fluids. The network is formed by cross-links between the polymeric constituents. These cross-links can either be physical or chemical. Chemical cross-linking methods have the advantage that the cross-linking density can easily be varied and with this also the mechanical properties of the final hydrogel. Physically cross-linked hydrogels are on the other hand adaptive and self-healing by nature. A combined chemically and physically cross-linked network could have highly interesting features from a self-healing materials point of view. In recent years, a number of chemical reactions have been utilized for hydrogel cross-linking. Since hydrogels hold great promise in a variety of biomedical applications, there is a need for novel cross-linking methods, especially those that are biocompatible. In this article, we describe the biocompatible cross-linking reaction SPAAC (strain-promoted azide-alkyne cycloaddition). In the SPAAC reaction, the highly selective reaction between a ring strained alkyne (BCN) and an azide simply occurs in water without any other additives. Poly(ethylene)glycol (PEG) hydrogels were successfully formed using SPAAC as the cross-linking method. We especially focussed on preparing soft hydrogels, mimicking the stiffness of soft body tissues. Confocal microscopy studies performed on the hydrogels revealed that gels containing the cell-adhesion peptide RGDS are a good substrate for cellular adherence. One of the disadvantages we encountered when using SPAAC was that it is hampered by slow reaction kinetics. Furthermore, an activatable cross-linking method is desired, especially in the field of injectable hydrogels. We therefore developed a novel cross-linking method which is both fast and activatable. This fast reaction between a catechol (DHPA) and BCN was called SPOCQ (strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition). The SPOCQ reaction only occurs upon oxidation of the DHPA (catechol) which can be performed both chemically and enzymatically. Both oxidation methods resulted in fast hydrogel formation. We showed that the SPOCQ and SPAAC reaction can be used in one pot, SPOCQ for the fast hydrogel formation and subsequently the SPAAC reaction for functionalization of these hydrogels. We also give an outlook on combining these chemical cross-linking methods with physical cross-linking by incorporation of the calcium-binding motif alendronic acid.