The increasing popularity of stem cells in life science research has at least two major causes. On one hand, the study of stem cells may provide insights into one of the major secrets of biology: the mechanisms of cell differentiation. On the other hand, stem cells are potentially promising tools for regenerative therapy. The understanding of how environmental stimuli are translated into phenotypic differentiation through gene expression changes and how the same stimuli at the same time may perturb the normal process of cellular differentiation, growth and maintenance is a central issue for fundamental research but is also essential for the development of efficient and safe procedures for therapeutic use. This article assembles the known facts, as pieces of a puzzle, into a coherent picture around the idea of why stem cells are so sensitive to their culture environment and what practical consequences this implies.