Celiac disease (CeD) is a chronic immuno-mediated enteropathy caused by dietary gluten with marked autoimmunity traits. The human leukocyte antigen (HLA) class II heterodimers represent the main predisposing factor, although environmental agents, as viral infection, gut microbiota, and dietary regimen, also contribute to CeD risk. These molecules are involved in autoimmunity as they present self-antigens to autoreactive T cells that have escaped the thymic negative selection. In CeD, the HLA class II risk alleles, DQA1*05-DQB1*02 and DQA1*03-DQB1*03, encode for DQ2.5 and DQ8 heterodimers, and, furthermore, disease susceptibility was found strictly dependent on the dose of these genes. This finding questioned how the expression of HLA-DQ risk genes, and of relative surface protein on antigen-presenting cells, might be relevant for the magnitude of anti-gluten inflammatory response in CeD patients, and impact the natural history of disease, its pathomechanisms, and compliance to dietary treatment. In this scenario, new personalized medical approaches will be desirable to support an early, accurate, and non-invasive diagnosis, and to define genotype-guided preventive and therapeutic strategies for CeD. To reach this goal, a stratification of genetic risk, disease outcome, and therapy compliance based on HLA genotypes, DQ2.5/DQ8 expression measurement and magnitude of T cell response to gluten is mandatory. IMPACT: This article revises the current knowledge on how different HLA haplotypes, carrying the DQ2.5/DQ8 risk alleles, impact the onset of CeD. This review discusses how the expression of susceptibility HLA-DQ genes can determine the risk assessment, outcome, and prevention of CeD. The recent insights on the environmental factors contributing to CeD in childhood are reviewed. This review discusses the use of HLA risk gene expression as a tool to support medical precision approaches for an early and non-invasive diagnosis of CeD, and to define genotype-guided preventive and therapeutic strategies.