Living organisms are made of wet, soft tissues. However, there is only one candidate to simultaneously replicate the mechanical and composition features of load-bearing tissues, that is, strain-stiffening hydrogels. The conventional mechanical match design principle is mostly limited to stiffness matching. However, this strategy cannot sufficiently and necessarily lead to mechanical matching over the whole physiologic deformation period for tissues and damages the tissues over time. In this review, we aim to provide a comprehensive summary of the reported synthetic strain-stiffening hydrogels and particularly focus on the relationship between their structure and performance. Initially, we present a brief introduction on the significance of strain-stiffening hydrogels in mimicking the mechanics of tissues, and then we discuss the qualitative evaluation of the strain-stiffening behaviors to guide the design of materials towards mimicking soft tissue. After distinguishing the mechanical testing methods, we focus on the methods for the preparation of typical strain-stiffening hydrogels based on categories, such as network without strand entanglement, semiflexible network, and anisotropic networks. Subsequently, we discuss the structural evolution of strain-stiffening hydrogels. We hope that this review will serve as an updated introduction and reference for researchers who are interested in exploring strain-stiffening hydrogels as tissue-mimics for addressing the societal needs at various frontiers.