Nature designs a vast library of soft materials in living bodies to fulfil many unique and specific functions, including strong mechanics, high actuation and sensitivity, better biocompatibility, and fast self-healing property. Sure nature soft materials offer a rich reservoir for rational design and engineering of synthetic soft materials (i.e. hydrogels). Synthetic polymer hydrogels as soft-wet materials, consisting of three-dimensional cross-linked networks and a large amount of water (50–90%), possess many unique properties such as swelling/deswelling, stimuli-responsiveness, shock absorption, and low sliding friction, making them as potential excellent biomimetics for substitution of soft living materials. However, conventional hydrogels often suffer from weak mechanical properties, which greatly limit their extensive uses for many other applications. In this talk, we will present different design strategies to prepare tough and multifunctional hydrogels with unconventional polymer network architectures and extraordinary properties. Guided by our design principle, we will demonstrate different hydrogels with high mechanical properties, self-healing, actuation, mechanoresponse, antifouling, and/or wound healing to mimic cartilages, artificial muscles, and mussel-inspired glues. In parallel, molecular simulations will be presented to given atomic-details of structure-properties relationship. Finally, several unique aspects for future development of tough hydrogels will be suggested.