Natural genetic diversity is a largely untapped reservoir for use in the discovery of stem cell regulatory pathways. Here we explore the means by which phenotypic diversity in mice can lead to the discovery of novel genes affecting stem cell regulation. We use as an example the discovery that latexin is a regulator of the natural size of the hematopoietic stem cell population in mice. The fact that it is a negative regulator of stem cell numbers, and thus served as a brake on stem cell expansion, led us to consider the possibility that it acts as a tumor suppressor. Experimental evidence supporting this hypothesis is reviewed.