Given the importance of stem cells to adult tissues, it has long been postulated that stem cells divide infrequently to preserve their long-term proliferation potential and to prevent the acquisition of errors during DNA replication. Yet, some stem cells must be able to continually churn out progeny in tissues that rapidly turn over or are subject to sudden injuries or growth spurts. This Review explores the challenges that mammalian stem cells face in balancing the competing demands of proliferation and differentiation in tissues.