The chemical engineering of nanostructures with atomic-scale precision is a fundamental scientific challenge. Cation exchange reactions in nanoplatelets (NPLs) offer an attractive platform for this precision chemistry, as it is relatively simple to carry out, extremely versatile, and allows the production of heterogeneous nanostructures that cannot be produced by any other means. A major hindrance has, however, been the lack of knowledge of the “weak spots” of the platelets where the ionic exchange reaction is initiated to optimally control the process toward directed nanoscale assemblies. Here, mercury selenide formation in cadmium selenide NPLs is investigated. The study of Cd_(1-n)Hg_nSe NPLs using scanning transmission electron microscopy (STEM) pinpoints at the corners (vertices) and edges of the NPLs as the exchanged sites. Comprehensive first principles density functional calculations of Hg substitution energies in a hierarchy of models of four monolayers (ML) CdSe NPL stabilized with acetate ligands unambiguously underscore that the energetically preferred exchange positions are platelet corners — in line with the experimental findings. The results thus not only explain in detail how the cation exchange process in 2D CdSe NPLs is kicked-off, but also establish an arena for future studies in 2D nanomaterials reaching far beyond these reactions.