Adult stem cells are essential to maintain regenerative tissues such as skin epidermis, gastrointestinal mucosa or the hematopoietic system. Recent studies in mice suggest that the transcription factor and oncoprotein c-Myc has unexpected functions during both self-renewal and the differentiation of stem and early progenitor cells, particularly in interactions between stem cells and the local microenvironment or ‘niche'. By incorporating recent findings on Myc and hematopoietic stem cells we propose a model in which ‘resting' hematopoietic stem cells are ‘activated' to self-renew and to differentiate at the interface between the niche and non-niche microenvironments.