Neurodegenerative diseases are a major challenge for aging societies, and the development of small, non-peptidic molecules with neurotrophic activity is of vital importance as such compounds easily cross the blood-brain barrier. We recently discovered that militarinone A (MiliA), a small fungal metabolite from Paecilomyces militaris, was able to stimulate neuronal outgrowth in PC12 cells within 24 hours (1). Application of MiliA to other cells such as the murine neuroblastoma cell line N2a, however, resulted in immediate onset of apoptosis. In summary, the fungal metabolite MiliA induces differentiation in PC-12 cells by persistant activation of pathways that are also involved in NGF-mediated differentiation, namely the PI3-K/PKB and the MEK/ERK pathways as well as by activation of the transcription factor CREB. The continuous activation of these pathways finally led to up-regulation of p53, release of AIF from mitochondria, and activation of the c-Jun/AP-1 transcription factor that was also described as a ‘killer on the transcriptional leash’ (2). Consequently, PC-12 cells succumbed to cellular death 48 to 72 hours post-treatment. Application of MiliA to other neuronal cells as N2a, however, resulted in immediate onset of apoptosis by nuclear translocation of AIF, and activation of caspases and c-Jun/AP-1. The main difference between these two cell types was found to be the basal expression of p53, being very high in N2a, but low in PC-12. It was recently reported that basal levels of p53 positively control production and mitochondrial accumulation of AIF (3). High expression of AIF could be an advantage for survival, as it helps to detoxify oxidative radicals as long as it is localised inside the mitochondria. But, on the other side, it pre-disposes these cells to a more efficient killing upon insults that affect mitochondrial integrity. N2a cells that showed a high expression of p53 fit into this category.