Abstract: The oil and gas resources from deep and ultra-deep reservoirs in China are the most important target of exploration and development. However, pervasive and ubiquitous wellbore instability in hard brittle deep shale seriously compromises the efficient development of deep and ultra-deep oil and gas resources. Wellbore instability in deep hard brittle shale under the chemo-mechanical coupling is a complicated problem involving multi-scale evolution among micro-scale, meso-scale and macro-scale. The basic principle of wellbore instability in hard brittle shale under chemo-mechanical coupling was briefly introduced. In addition, the previous studies on the mechanism between hard brittle shale and drilling fluid, quantitative description of the evolution of damage in mesocosm structures, macroscopic mechanical deterioration of shale after hydration, and quantitative analysis of wellbore stability, were reviewed in terms of micro-scale, meso-scale and macro-scale. Moreover, a new idea was proposed for wellbore stability in hard brittle shale from the perspective of fracture mechanics considering chemical effects.