We have previously shown that tissue inflammation in the brain can potently inhibit neural stem cell activity and prevent the production of new neurons. In this study, we examine the specific influence of an inflammatory signaling molecule called tumor necrosis factor alpha (TNFa). TNFa is one of the primary pro-inflammatory signaling molecules that establishes and maintains damaging inflammation and we speculated that blocking TNFa may protect stem cells under conditions where injury or degeneration causes inflammation. TNFa can also be beneficial in certain contexts and here we show that the effects of TNFa on stem cells and neurogenesis can be either detrimental or beneficial, depending on whether TNF signals through TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2). Loss of TNFR1 promoted stem cell survival and neurogenesis while loss of TNFR2 was detrimental to stem cells and neurogenesis. Loss of TNFa itself had mixed effects and was ultimately not protective. This illustrates how a single molecule can have multiple roles in neural stem cell biology and cautions against the uninformed use of clinically-approved TNFa blocking agents in an attempt to protect stem cells and neurogenesis in the context of inflammation caused by neurodegenerative disease or brain injury.