Primary neuronal cultures are commonly used to dissect the molecular and cellular mechanisms that underlie human brain diseases. Neurons dissociated from an embryonic brain and grown in culture dishes are almost by definition different from those residing inside a living brain. Not only are the individual cells stripped of their normal chemical and physical contacts, but the cellular composition of the cultures (the ratio of cell types) can be affected by many intrinsic and extrinsic factors, including brain region, neuronal birthday, gender, genetic background and in vitro age. Changes in any of these factors may have a strong impact on the outcome of the experiment. In a recent study, Romito-DiGiacomo et al. /54/ demonstrated that when neurons were harvested from murine embryonic cortex, the typical protocol favored cells that were just finishing cell division at the time of harvest. By taking advantage of the fact that the date of the final cell division (birthday) of a neuron correlates with its final position in the cortical plate they were able to assay deeper layer neurons (layers V-VI) separately from the more superficial layers (layers II-III). They reported that while the superficial cells were sensitive to the toxic effect of beta-amyloid, the deeper layer neurons were virtually resistant to death in its presence. The findings recapitulate selective vulnerability in the neocortex of Alzheimer's disease. This is a beautiful example of how to turn the apparent weakness of primary cultures into strength through experimental design and data interpretation. Selective vulnerability is a common feature of neurodegenerative disease, thus it is critical to use the right primary culture. Do you know what is in your culture?