Mixed ionic and electronic conducting perovskites that can readily exchange oxygen with the atmosphere exhibit a chemo-mechanical coupling between their oxygen content and their lattice dimensions. The lattice dilation accompanying oxygen loss, termed “chemical expansion,” beneficially enables new techniques that use measures of strain to determine changes in oxygen content, but deleteriously causes large chemical stresses in devices during operation that can lead to mechanical failure. In this presentation I will describe our work aimed at understanding, across multiple length scales, which factors impact chemical expansion coefficients in perovskites, in order to develop design principles for controlling them. Polycrystalline gallate and titanate perovskites containing multivalent Ni, Fe, and Co have been studied using in situ thermogravimetry, diltometry, and diffraction to probe the chemical expansion process at macroscopic and crystal structure levels. Corresponding simulations using density functional theory, molecular dynamics, and empirical approaches have provided atomistic insight into changes taking place on the anion and cation sublattices during oxygen loss. Factors impacting the magnitude of the chemo-mechanical coupling, including oxygen vacancy radii, charge localization on cations, temperature, crystal symmetry, and defect ordering, have been identified.