R-spondins (RSPOs) are secreted cysteine-rich glycoproteins that belong to a superfamily of thrombospondin
type 1 repeat-containing proteins. RSPOs together with WNT proteins potentiate canonical WNT/β-catenin
signaling activity. Over the last several years, the understanding of the regulatory mechanisms and functional
roles of RSPOs in many biological contexts has increased. Particularly, because a leucine-rich repeat containing
G protein-coupled receptor 5 (LGR5), a stem cell marker originally identified as a marker for intestinal stem
cells, and two closely related proteins, LGR4 and LGR6, were identified as cognate receptors for RSPOs, significant research progress has been made in understanding the functional roles of RSPO/LGR signaling in stem
cell biology. Given the crucial roles of canonical WNT signaling in self-renewal and differentiation of various
types of stem cells, examination of RSPO function and underlying mechanism in these stem cells has provided
new insight into the regulatory roles of WNT signaling in stem cell behavior. In this review, we summarize and
discuss recent advances in the understanding of the signaling mechanism and roles of RSPOs in different stem
cell contexts.