Nanocrystalline cobalt spinel has been recognized as a very active catalytic material for N2O decomposition. Its catalytic performance can be substantially modified by proper doping with alien cations with precise control of their loading and location (spinel surface, bulk, and spinel-dopant interface). Various doping scenarios for a rational design of the optimal catalyst for low-temperature N2O decomposition are analyzed in detail and the key reactivity descriptors are identified (content and topological localization of dopants, their redox vs. non-redox nature and catalyst work function). The obtained results are discussed in the broader context of the available literature data to establish general guidelines for the rational design of the N2O decomposition catalyst based on a cobalt spinel platform.