A simplified flow diagram illustrating an approach to isolating, identifying and developing plant health promoting endophytes. This example involves apple replant disease (ARD), a complex phenomenon describing the detrimental physiological and morphological reaction of apple trees in sites that have been repeatedly planted with apple, which can cause a shift towards soil microbiome dysbiosis. The four apple plants on the left show stunting from being grown in pots containing ARD soil, and the four apple plants on the right show good growth and health from being grown in non-ARD soil. Root endophyte and rhizosphere diversity of ARD and non-ARD soils and plants is characterized and compared using a combined approach involving metabarcoding and culturing. Potential pathogens, causal agents and indicators of dysbiosis are identified in ARD samples, and potential mutualists are inferred from non-ARD samples. Mutualistic individuals or consortia are selected as possible ARD biocontrol agents and investigated for their antagonism against ARD-associated pathogens, protective secondary metabolites, plant health promoting interactions and other attributes. Beneficial rhizosphere strains and/or endophyte(s) are then inoculated into soil and/or apple plants for further study, including challenge trials involving inoculated apple planted in ARD soils.