The discovery of neurogenesis and neural stem cells (NSC) in the adult CNS has overturned a long-standing and deep-routed “dogma” in neuroscience, established at the beginning of the 20th century. This dogma lasted for almost 90 years and died hard when NSC were finally isolated from the adult mouse brain. The scepticism in accepting adult neurogenesis has now turned into a rush to find applications to alleviate or cure the devastating diseases that affect the CNS. Here we highlight a number of methodological, technical and conceptual drawbacks responsible for the historical denial of adult neurogenesis. Furthermore, we discuss old and new issues that need to be faced before NSC or endogenous neurogenesis can safely enter into the doctor's bag for therapies. BioEssays 30:135–145, 2008. © 2008 Wiley Periodicals, Inc.