Whereas many techniques exist to detect HLA antibodies in the sera of immunized individuals, assays to detect and quantify HLA-specific B cells are only just emerging. The need for such assays is becoming clear, as in some patients, HLA-specific memory B cells have been shown to be present in the absence of the accompanying serum HLA antibodies. Because HLA-specific B cells in the peripheral blood of immunized individuals are present at only a very low frequency, assays with high sensitivity are required. In this review, we discuss the currently available methods to detect and/or quantify HLA-specific B cells, as well as their promises and limitations. We also discuss scenarios in which quantification of HLA-specific B cells may be of additional value, besides classical serum HLA antibody detection.