The increasing speed of global environmental change, e.g. climate warming, precipitation regimes, severe droughts and flooding, and increasing anthropogenic disturbances have a far-reaching impact on plant-microbe interactions and plant defense chemistry. Ecosystems rely on these interactions to be functioning effectively, to be productive in crop production and to be resilient. Plants respond directly to environmental stressors, and the ecology and stability of the microbial community (microbiomes) inhabiting the rhizosphere, phyllosphere, and endosphere is also transformed by environmental stressors. Microbial symbionts like mycorrhizal fungi, fixation of nitrogen-containing bacteria and growth-promoting endophytes are major controlling factors in plant nutrition, stress resistance, and immunological competence. Environmental changes tend to alter the organization and activity of these microbiomes, which may undermine mutualistic advantages and change host defensesignaling pathways. Abiotic stress and microbial cues contribute to modulation of plants reacting with both constitutive and induced chemical defenses such as phytoalexins, volatile organic compounds, and reactive oxygen species. The knowledge of the impacts of stressors on microbial stability and the management of plant chemical defense is of a vital concern to sustainable agriculture and ecosystem stability. This review summarizes the current research on these interdependent dynamics, identifies existing knowledge gaps, methodological developments and future directions of research.