The introduction 60 years ago of clonal methods to identify individual hematopoietic cells with stem cell properties at frequencies of <10-5 revolutionized approaches to elucidating how many tissues with a high cell turnover maintain their numbers throughout adult life. Early examples included the mammary gland as well as the blood of humans and mice. More recent advances in methods to correlate unique phenotypes of rare, biologically characterized viable single cells with their proteomic and epigenomic properties has allowed a previously unanticipated degree of heterogeneity to be revealed among primitive cell types in these tissues. These studies have also led to evidence of new levels of complexity and diversity in how the survival, growth and differentiation of these primitive cells can be regulated. In addition, the development of methods to track large numbers clonal populations of human cells in transplanted immunodeficient mice before and after their rapid and efficient de novo transformation with defined oncogenes is introducing a new era for examining the entire process of human leukemogenesis and breast cancer development. This talk will try to summarize the highlights of recent progress from our lab along these emerging avenues of investigation.