Given environmental, economic, and social costs of unilateral chemical and biotechnological interventions to control pests, there is an urgent need to transition towards a knowledge-intensive holistic approach emphasizing agroecosystem design and management. The focus will be on what makes agroecosystems susceptible and vulnerable to insect pests, pathogens and weeds, in order to design diversified agroecosystems that prevent and suppress insect pest, pathogen and weed problems. We propose a plant health model applicable to agroecosystems that feature biodiversity enhanced designs and soils rich in organic matter and microbial life, managed with low chemical loads. In such diversified farming systems, the general protection of the plant is a consequence of mutualistic above and below ground relationships between plants, insects, and soil microbial communities. From a practical standpoint, the approach involves (a) restoring plant diversity at the landscape and field level, with spatial and temporal crop combinations that deter pests and/or enhance natural enemies and (b) increasing soil organic matter through green or animal manures, compost and other amendments, which enhance antagonists that control soilborne pathogens. Polycultures promote a complex root exudate chemistry which plays an important role in recruitment of plant-beneficial microbes, some of which enhance plants’ innate immune system. Unleashing biotic interactions between plant diversity and increased microbial ecological activity generate conditions for the establishment of a diverse and active beneficial arthropod and microbial community above and below ground, essential for pest/disease regulation.