Abstract: The NKG2D receptor-ligand axis is a major pathway through which natural killer (NK) cells and subsets of effector T cells recognize stressed or malignant cells; thus, it plays an important role in immune surveillance, immune evasion and therapeutic responses in solid tumors. During tumor initiation and progression, however, tumor cells can reduce the density of membrane-bound ligands through epigenetic silencing, protease-mediated ligand shedding, and exosome release, and the tumor microenvironment further induces downregulation of the receptor on effector cells. These processes collectively disrupt the function of the NKG2D axis and promote tumor immune evasion. In recent years, translational efforts targeting these barriers have mainly included NKG2D ligand-targeting agents, NKG2D-engineered cell therapies, and NKG2D-related NK cell engagers, which act at different levels, including ligand stabilization, restoration of effector-cell cytotoxicity, and recruitment and activation of endogenous effector cells. Current developments indicate a trend toward stratified and combinational application on the basis of ligand status, effector-cell function, and microenvironmental features. This review summarizes the immune evasion mechanisms of NKG2D axis-mediated immune evasion in solid tumors and the recent progress in its therapeutic translation, with particular focus on comparing the major advantages and limitations of different treatment strategies and discussing key issues in their clinical translation.