Microbial inoculants are critical for sustainable crop production in dryland agriculture. However, several limitations (drought, heat, salinity, nutrient deficiency, etc.) of drylands and soil variability limit their consistent performance. Climate, soil properties (pH, texture, etc.), and their interactions are strong filters for microbial communities, functions, and activities across multiple scales, regions, and ecosystems. This review discusses several considerations of the peculiarities of drylands that must be factored into microbial formulations and inoculations decisions. Blanket/universal microbial formulations, inoculation methods, timings, and rates generally approach microbial, plant, and soil functions in isolation. This masks the complex microbial, soil, plant, environmental interactions, and varying stressors that characterize dryland agroecosystems. To this end, the critical considerations synthesized in this review are to: (1) contextualize microbial strain selection and formulation; (2) contextualize inoculation strategies (timing, methods and rates) to ensure survival and optimum efficacy; (3) establish how soil chemistry, texture, and micro-climate interactively shape plant-microbe interactions; and (4) manage the dynamic synergistic convergence of microbial inoculants with native microbial communities and host plant physiology to build holistic plant-soil-microbe continuum resilience. This requires co-formulating microbial inoculants with crop genotypes and tailoring inoculation strategies to specific dryland contexts. Microbial inoculants should not be viewed and/or implemented in isolation. Further, the fate and persistence of microbial inoculants is currently highly variable and not consistently measured causing interpretive ambiguity. Future studies should address these aspects. These considerations are therefore critical for leveraging microbial inoculants for sustainable dryland agriculture.