<p>Anisotropy is a fundamental physical characteristic that influences efficient cell migration in biological systems. Concurrently, anisotropy serves as a primary factor contributing to a significant accumulation of mechanical stress within migrating epithelial collectives, provided that the cells maintain the strong E-cadherin-mediated cell-cell adhesion contacts that are characteristic of epithelial cells. While cells are capable of effectively enduring both compressive and tensile stress, the shear stress that can be generated during a physiological process such as collective cell migration poses a risk of: (i) disrupting the adhesion contacts among cells and between cells and the extracellular matrix, (ii) causing a partial disintegration of the lipid bilayer and cytoskeleton, (iii) triggering cellular inflammation, and (iv) inducing changes in gene expression. The principal aims of this theoretical analysis are: (i) to emphasize the main characteristics of isotropic and anisotropic wetting/de-wetting of migrating epithelial collectives as the main factor in mechanical stress generation; (ii) to formulate a constitutive model of the anisotropic viscoelasticity of migrating epithelial and mesenchymal collectives; (iii) to emphasize the physical factors related to cell sensitivity to shear stress; and (iv) to explore potential cellular strategies to mitigate shear stress, while also highlighting the associated costs of these strategies.</p>