The RUNX genes encode conserved transcription factors that play vital roles in the development of various animals and human diseases. Recent studies by a few groups including ours have demonstrated that this gene family, as represented by a single ortholog designeated rnt-1, also occurs and plays intriguing roles in the simple model organism, Caenorhabditis elegans. Our genetic and molecular analyses revealed that rnt-1 is allelic to mab-2, which had previously been known to cause an abnormal development of the male tail. rnt-1 was further shown to be predominantly expressed in the stem cell-like lateral seam hypodermal cells. These cells are characterized by their abilities to undergo stem cell-like asymmetric divisions giving rise to self-renewing seam cells and various differentiated descendants of hypodermal and neuronal fates. We found that rnt-1 mutants exhibit an impaired asymmetry in the division of T cells, the posterior-most member of the seam cells. Mutant analysis indicated that rnt-1 is involved in regulating T blast cell polarity in cooperation with the Wnt signaling pathway. On the other hand, Nimmo et al. independently discovered that rnt-1 acts as a rate limiting regulator of cell proliferation in the seam cells, V1-6. In this review, we will outline these new findings and discuss their general implications in the mechanism of coordination between proliferation and differentiation of stem cells. J. Cell. Biochem. 100: 1119–1130, 2007. © 2007 Wiley-Liss, Inc.