Rapid improvement of the stability of metal halide perovskite materials is required to enable their adoption for energy production at terawatt scale. To understand the role of the active layer stability in these devices we use in situ X-ray diffraction to observe the evolution in structural stability across mixed A-site APbI3 materials where the A-site is a combination of formamidinium, Cs, and/or methylammonium. During device operation we observe spatial de-mixing and phase segregation into more pure constituent phases. Using complementary first-principles calculations of mixed A-site halide perovskites, a hypothesized framework explaining the experimentally observed mixing and de-mixing in these systems is presented and then validated using in situ X-ray diffraction and spatially resolved time of flight secondary ion mass spectrometry. Taken together, these results indicate that stability is not only a function of device architecture or chemical formulation, but that the processing strategy is critically important in synthesizing the most energetically favorable state and therefore the most stable device systems. This study reconciles disparate reports within the literature and also highlights the limitations of shelf life studies to ascertain stability as well as the importance of testing devices under operational conditions. © 2019 The Royal Society of Chemistry.