Every experience has a neurochemical foundation. Even the slightest alteration in the brain's accustomed neurochemistry therefore has the potential to elicit unusual experiences that might have strikingly spiritual qualities. This chapter draws upon recent studies in neuroscience to help understand the link between the “chemistry of consciousness” and episodes of religious innovation throughout American history. From Native American peyotism to the role of psychedelics in the 1960s counterculture movement, there have been clear and identifiable neurochemical substrates to Americans' quest for religious ecstasy.