Mechanical properties of a class of self-assembling hydrogels based on DNA hybridization were studied using rigid, embedded inclusions. Because inclusions can be deflected without direct contact with a manipulator (e.g., magnet) once they are embedded within the subject material, the measurement technique is well suited for monitoring instantaneous and time-varying changes in the mechanical properties of active materials as they respond to external stimuli. In gels crosslinked with complementary strands of oligonucleotides, hybridization chemistry and strand displacement mechanisms allow reversible assembly, shape change, and large changes in compliance through the application of particular strands of DNA. In earlier work using large (diameter ∼0.8 mm) magnetic beads, the scaling behavior of the global elastic modulus with crosslink density was determined. More recently, it was shown that a threefold increase in stiffness was possible by generating prestress in the DNA-crosslinked gel network. Currently, the gels are functionalized to support cell attachment and embedded with micro-fabricated nickel bars. Through the measurement of local elastic and shear moduli as well as Poisson’s ratios, cell-substrate interactions can be used as a means of evaluating the potential of DNA-crosslinked gels as active cellular engineering substrates and tissue engineering scaffolds.