Most adult tissues contain a reservoir of adult stem cells that maintain homeostasis. Loss of stem cell function can lead to severe tissue dysfunction, accelerated aging, and cancer. We study epidermal stem cells (epSCs) as a model of adult stem cell function. In steady state conditions, epSCs express high levels of ¨molecular breaks¨ that make them refractory to activating stimuli, remaining quiescent, unspecified, and strongly adhered to their niche. However, epSCs can eventually respond to such stimuli thus egressing the niche, and feeding into the differentiated compartment. It is not known yet why some stem cells respond to activating stimuli or what is the nature of this stem cell heterogeneity. Tilting the balance towards excessive or reduced stem cell response may cause premature aging, lack of regenerative potential, or carcinogenesis. We have identified the molecular clock as a possible mechanism regulating epSC function. We hypothesize that epSC heterogeneity is due to a molecular oscillator that establishes their refractory or permissive state towards stimuli. The questions we aim to answer are: How does the clock machinery establish populations of stem cell at different states at the systems level, and how this is deregulated in carcinomas. To address these we will disrupt the clock in epSCs in vivo to study the consequences over homeostasis and carcinogenesis; we will use fluorescent reporter mice to monitor the stem cell clock during homeostasis and tumor progression; we will FACS purify stem cells at different clock states in vivo, and deep sequence their entire transcriptome to study their molecular characteristics; and we will study any correlations between the clock and grade, chemotherapy response, and clinical outcome of human squamous carcinomas. We expect to uncover a novel mechanism for stem cell regulation in tissues which disrupted may lead to tissue dysfunction and pathology.