Nerve growth factor (NGF) and its receptors are best known for regulating development in the mammalian nervous system. Now, on p. 5185, Coppola and colleagues use a reverse conditional gene targeting strategy in mice to show that the NGF/TrkA receptor system also modulates immunological functions. Previous work has hinted that NGF/TrkA is required for a healthy immune system. Immunodepletion of NGF in mice, for example, causes major immunological abnormalities. However, this phenotype could be indirectly caused by neural system abnormalities rather than by intrinsic effects of NGF/TrkA on the immune system. To distinguish between these possibilities, the researchers genetically activated TrkA in the neuronal structures only of TrkA-null mice. The result: grossly normal mice containing all the major immune system cell populations, but with defects in immunoglobulin production and B cell number with aging. Thus, although the NGF/TrkA system is dispensable for lymphoid system development, it directly modulates immunological functions in adult animals.