In this essay I critically examine the role of entropy of mixing in articulating a macroscopic criterion for the sameness and difference of chemical substances. Consider three cases of mixing in which entropy change occurs: isotopic variants, spin isomers, and populations of atoms in different orthogonal quantum states. Using these cases I argue that entropy of mixing tracks differences between physical states, differences that may or may not correspond to a difference of substance. It does not provide a criterion for (...) the sameness and difference of substance that is appropriate to chemistry. (shrink)