Cancer stem cells have now been recognized in a wide variety of human tumors. The existence of cancer stem cells poses both tremendous challenges and tantalizing potential for our ability to successfully combat cancer. This Keystone Symposia meeting aims to bring together scientists who are interested in better understanding the mechanisms by which cancer stem cells contribute to tumor heterogeneity, self-renewal and drug resistance. One area of emphasis will be intercellular communication. Cellular context and microenvironment establish the tumor niche and shape the interaction of the tumor with the immune system. In addition, developmental signal transduction pathways such as Hippo, Notch and Wnt, frequently deregulated in cancer, increasingly offer tangible opportunities for therapeutic intervention. Another important area of emphasis will be efforts to better understand the mechanisms and importance of tumor heterogeneity. Techniques such as clonal analysis and barcoding are shedding important light on the interplay between tumor evolution, differentiation, miRNA control and epigenetics. This is an era of rapid progress in understanding cancer stem cell biology with great potential to benefit human health.