The clinical relevance of humoral allosensitization has gained a lot of attention in the last few years. An increasing number of studies have demonstrated adverse graft survival in patients who have either preformed or post-transplant-developed anti-HLA antibodies. The detection of HLA antibodies and the specificity analysis have evolved over time from primarily cell-based to solid-phase methods, including the availability of single-HLA antigen preparations. These technological advances combined with a better understanding of the epitope structure of HLA antigens have provided a more efficient, structurally based strategy to determine HLA compatibility. In conclusion, these emerging approaches can be reliably used to predict crossmatch results in highly sensitized patients and also to monitor the development of clinically relevant anti-HLA antibody after transplantation.