Antibody-mediated rejection is the leading cause of kidney allograft loss. Although considerable experimental and clinical evidence suggests a causal effect of circulating HLA-DSAs in antibody-mediated rejection and allograft failure, HLA-DSAs induce a wide spectrum of injuries to the allograft that illustrate the need to delineate the characteristics of HLA-DSAs that confer pathogenesis. Current risk stratification is based on HLA-DSA characteristics, including antibody specificity, HLA class, and strength. Recently, the complement-binding capacity of HLA-DSAs has been recognized as a clinically relevant marker for predicting pathogenicity and allograft loss. Emerging data also support a role for HLA-DSA IgG subclass composition in discriminating distinct patterns of antibody-mediated injury. This progress in our understanding of HLA-DSA pathogenicity provides new tools to stratify individual immunological risks. However, specific prospective studies addressing immunological risk stratification in large and unselected populations are required to define the clinical benefit and cost–effectiveness of such a comprehensive assessment of HLA-DSAs before implementation in current clinical practice.