The tolerance of normal brain tissues limits the radiation dose that can be delivered safely during cranial radiotherapy, and one of the potential complications that can arise involves cognitive impairment. Extensive laboratory data have appeared recently showing that hippocampal neurogenesis is significantly impacted by irradiation and that such changes are associated with altered cognitive function and involve, in part, changes in the microenvironment (oxidative stress and inflammation). Although there is considerable uncertainty about exactly how these changes evolve, new in vitro and in vivo approaches have provided a means by which new mechanistic insights can be gained relevant to the topic. Together, the data from cell culture and animal-based studies provide complementary information relevant to a potentially serious complication of cranial radiotherapy and should enhance our understanding of the tolerance of normal brain after cranial irradiation.