Regioselective chemical reactions and structural transformations of two-dimensional (2D) layered transition-metal chalcogenide (TMC) nanocrystals are described. Upon exposure of 2D TiS2 nanodiscs to a chemical stimulus, such as Cu ion, selective chemical reaction begins to occur at the peripheral edges. This edge reaction is followed by ion diffusion, which is facilitated by interlayer nanochannels and leads to the formation of a heteroepitaxial TiS2–Cu2S intermediate. These processes eventually result in the generation of a single-crystalline, double-convex toroidal Cu2S nanostructure. Such 2D regioselective chemical reactions also take place when other ionic reactants are used. The observations made and chemical principles uncovered in this effort indicate that a general approach exists for building various toroidal nanocrystals of substances such as Ag2S, MnS, and CdS.