Soil microbiomes are known to influence the growth and hardiness of plants, making plant microbiome optimization a promising approach to enhancing plant performance. We consider methods for designing experiments to direct plant microbiome evolution, with the goal of increasing plant performance under drought conditions. Advantageous plant traits are selected and used to iteratively guide the microbiome development process across multiple generations of plants. Trait selection, physical implementation constraints, and the sequential structure of the study present unique challenges to the experimenter. We provide an overview of these challenges, along with the design of experiment strategies used to mitigate them. Additionally, we consider the advantages that innovative adaptation of design of experiments provides in the study of plant performance under reduced water conditions, a topic that is essential to understand for meeting future food demand of an increasing population in a changing climate.