Linheng Li is best known for using combined genomics and genetics to study stem cells and their associated niches in hematopoietic and intestinal tissues. He was among the first to identify the endosteal (osteoblastic lining cell) niche in supporting hematopoietic stem cell (HSC), the first cellular component of niche identified in a mammalian system. Based on the study of different HSC subpopulations, he was also among the first to propose a model of co-existing reserve pool and active adult stem cells in the same tissue in mammals. This concept not only provides an explanation for controversial observations of both quiescent and cycling stem cells in mammals, but also accounts for some aspects of drug resistance in cancer. Linheng has contributed to the field by characterizing and demonstrating the roles of several developmental signaling pathways in regulation of stem cells. These include: FGF, IGF, and Notch, and the reciprocal (yin and yang) roles of BMP and Wnt signaling affecting self-renewal; the roles of PTEN in controlling quiescence by inhibiting PI3K-Akt signaling, and in distinguishing normal stem cells from cancer stem cells; the role of PI3K-Akt in coordination with Wnt-β-catenin to promote HSC self-renewal in vivo and expansion in vitro; and, the role of non-canonical Wnt signaling in maintaining quiescent stem cells. His recent work shows a critical role of epigenetic (via DNA methylation and non-coding RNA) regulation of H19-Igf2 imprinted locus in controlling quiescent versus active states of HSCs, as well as Gtl2 maintaining primitive stem cells via suppression of mitochondrial biogenesis and metabolism.