The ancient messenger molecule hydrogen sulfide (H2S) modulates myriad signaling cascades and has been conserved across evolutionary boundaries. Although traditionally known as an environmental toxin, H2S is also synthesized endogenously to exert modulatory and homeostatic effects in a broad array of physiologic functions. Notably, H2S levels are tightly physiologically regulated, as both its excess and paucity can be toxic. Accumulating evidence has revealed pivotal roles for H2S in neuroprotection and normal cognitive function, and H2S homeostasis is dysregulated in neurodegenerative conditions. Here, we review the normal neuroprotective roles of H2S that go awry in Alzheimer’s disease, the most common form of neurodegenerative disease.