We have investigated cation exchange reactions in copper selenide nanocrystals using two different divalent ions as guest cations (Zn2+ and Cd2+) and comparing the reactivity of close to stoichiometric (that is, Cu2Se) nanocrystals with that of nonstoichiometric (Cu2-xSe) nanocrystals, to gain insights into the mechanism of cation exchange at the nanoscale. We have found that the presence of a large density of copper vacancies significantly accelerated the exchange process at room temperature and corroborated vacancy diffusion as one of the main drivers in these reactions. Partially exchanged samples exhibited Janus-like heterostructures made of immiscible domains sharing epitaxial interfaces. No alloy or core-shell structures were observed. The role of phosphines, like tri-n-octylphosphine, in these reactions, is multifaceted: besides acting as selective solvating ligands for Cu+ ions exiting the nanoparticles during exchange, they also enable anion diffusion, by extracting an appreciable amount of selenium to the solution phase, which may further promote the exchange process. In reactions run at a higher temperature (150 degrees C), copper vacancies were quickly eliminated from the nanocrystals and major differences in Cu stoichiometries, as well as in reactivities, between the initial Cu2Se and Cu2-xSe samples were rapidly smoothed out. These experiments indicate that cation exchange, under the specific conditions of this work, is more efficient at room temperature than at higher temperature.