Biological materials have evolved to combine a number of functionally relevant properties. They are sensitive to chemical and mechanical signals and respond to these signals in a highly specific manner. Many biological hydrogels possess the ability to stress-stiffen, a property that is difficult to mimic in synthetic systems. A novel synthetic hydrogel is described that possesses stress-stiffening behavior in the biologically relevant stress regime and, at the same time, contains DNA cross-links as stimuli-responsive elements. The hydrogel scaffold is composed of oligo(ethylene glycol)-functionalized polyisocyanopeptides (PIC), which show a sol-to-gel transition upon increasing the temperature. It is shown that the mechanical properties of the hybrid hydrogel depend on DNA cross-linker concentration and temperature. At high temperature, a hydrophobically bundled stress-stiffening PIC network forms. By contrast, gel formation is controlled by DNA cross-linking at temperatures below the PIC sol-to-gel transition. The DNA cross-linked hydrogel also exhibits stress-stiffening behavior and its properties are controlled by the DNA cross-linker concentration. The hydrogel properties can further be tuned when using DNA cross-linkers with different melting temperature or when breaking cross-links by strand displacement. This clearly shows the potential of DNA cross-links as stimuli-responsive elements, highlighting the possible applications of this hybrid hydrogel as a new sensor.