Lipotoxicity involves pathological alterations to cells and tissues in response to elevated fat levels in blood. Furthermore, this process can disturb both cellular homeostasis and viability. In the current study, the authors show that neural progenitor cells (NPCs) are vulnerable to high levels of palmitic acid (PA) a saturated fatty acid. PA was found to cause cell death associated with elevated reactive oxygen species (ROS) levels, and to reduce NPCs proliferation. To evaluate the lipotoxicity of PA in adult NPCs in the hippocampus, male C57BL/6 mice were divided into two groups and maintained on either a normal diet (ND) or PA-rich high fat diet (HFD) for 2 weeks. Interestingly, short-term PA-rich HFD feeding reduced the survival of newly generated cells in the hippocampal dentate gyrus and hippocampal brain-derived neurotrophic factor levels. These findings suggest PA has a potent lipotoxicity in NPCs and that a PA-rich HFD disrupts hippocampal neurogenesis.