An improved understanding of stem cell differentiation is critical for progress in regenerative medicine. It is an emerging view that a relatively small number of intracellular signaling mechanisms play particularly important roles in differentiation control. As one may expect, these pathways are highly evolutionarily conserved, used in many tissues and iteratively during differentiation of a particular tissue. The Notch signaling system is one pathway meeting these criteria. In many cases, Notch signaling keeps stem/progenitor cells undifferentiated, although it can in some cellular contexts be instructive for differentiation toward a particular fate. Here, we review our current understanding of how Notch controls cellular differentiation in various organs and how Notch integrates with other major signaling pathways, primarily focusing on Notch signaling in mammals. Given the importance of Notch in many stem cell fate decisions, the possibility of experimentally manipulating Notch signaling opens up new avenues to control stem cell differentiation.