The mammalian physiology represents a level of sophistication in materials design, assembly, and function that has yet to be replicated by the modern tools of materials science. Although, the building blocks of our body (pluripotent stem and progenitor cells) are still available within our tissues, the absence of the biological and structural cues that drove the development process early on, in an adult, limits our ability to regenerate after an injury. The goal of regenerative medicine is therefore to recapitulate embryonic events within an artificially defined materials space (i.e., the niche) so that the repair processes can be triggered using our reservoir of stem cells. This engineering of the regenerative niche will require an interdisciplinary exercise involving materials scientists, biologists, and clinicians. The success of this exercise will hinge on our ability to develop materials that incorporate principles of wound healing, lessons from immunology and developmental biology, and knowledge of cellular mechanics and molecular biology such that they can mimic the cellular environment, instruct cells to make fate decisions, and direct the hierarchical organization of tissues. This article presents the current state of this challenge in the implementation of regenerative therapies.