Chemistry, the science of substances and their transformations with roots in antiquity, provides as rich a source as any of the claims about what is not directly observable in the light of ideas reflecting both constancy and change. An important distinction in chemistry is that between macroscopic and microscopic realms, mistaken by positivists as a distinction between observable and theoretical and later by certain realists as a distinction between the merely superficial and the deeply theoretical. Recent realist themes about the preservation of the extension of substance predicates typified by “water” and the view that 20th-century scientific atomism vindicates earlier philosophical speculations about the corpuscular constitution of matter are unjustified. The relation between quantum and general chemistry is vexed. Despite questioning particular realist theses, however, none of this raises doubts about the basic realist stance that science seeks and sometimes achieves knowledge of a world independent of our thoughts.