Biomolecule-sensitive hydrogels that undergo volumetric changes in response to a target biomolecule such as glucose and proteins have become increasingly important because of their potential applications as smart biomaterials for constructing self-regulated drug-delivery systems (DDSs) and diagnostic systems. However, there have not been so many studies on biomolecule-sensitive hydrogels, due to difficulties in combining biomolecular recognition abilities with responsive functions within a hydrogel. This chapter introduces some strategies for designing biomolecule-sensitive hydrogels that exhibit swelling/shrinking behavior or sol-gel transition in response to the concentration of a target biomolecule. A standard strategy is to combine the molecular recognition events of biomolecules such as enzymes, lectins and antibodies with responsiveness of pH- and temperature-sensitive polymers. Another strategy uses biomolecular complexes like those of lectin-saccharide and antigen-antibody as dynamic cross-links of hydrogel networks. Designs of biomolecule-sensitive hydrogels will contribute significantly to develop smart DDSs in which specific amounts of drugs can be administered with monitoring specific biomolecules as diagnostic signals for several physiological changes. This chapter provides an overview of important researches about biomolecule-sensitive hydrogels for DDSs and diagnosis, focusing on saccharides, proteins, DNAs, etc. as target biomolecules.