In contrast to non-mammalian vertebrates, mammals and humans have limited innate capacity for the self-regeneration of tissues and organs owing to differences in genetics, development, immune systems and tissue complexity. Endogenous stem cells are tissue-specific adult stem cells with the capacity to self-renew and differentiate into specific cell types. Therefore, endogenous stem cells are being explored for the regeneration of tissues in situ and in vivo. Stem cells reside in specific niches in the body, and stem cell activation depends on progressive changes in the niche. Niches are specific and instructive microenvironments that can be recreated using biomaterial-based scaffolds. Such scaffolds can be fabricated into a variety of shapes and formulations, and they can be functionalized with biochemical and biophysical cues to guide stem cell fate and migration. In this Review, we discuss important differences in the self-regeneration abilities of non-mammalian vertebrates and mammals, including humans, and investigate adult stem cell populations and their niches involved in tissue repair and regeneration. We highlight natural and synthetic biomaterials and their potential for improving applications of endogenous stem cells and examine the role of interspecies chimaeras in regenerative medicine.