A major stimulant of allograft rejection is recipient T cell recognition of human leucocyte antigens in the donor kidney. Preforemed donor-specific HLA antibodies resulting in hyperacute rejection were first detected in 1969 by the complement-dependent cytotoxicity crossmatch assay; widespread application of this test detected higher titer donor-specific antibodies and reduced hyperacute and early accelerated rejection episodes. Evolution to flow cytometry cross-matching offers improved sensitivity for low titer but nonetheless, pathogenic antibodies. Newer immunoassays (using ELISA plates or microsphere technology), where purified HLA antigens are covalently bound to a solid-phase platform, have further improved sensitivity and specifity of HLA antibody detection. Despite advancements in technology, newer solid-phase assays have a number of interpretive considerations that must be appreciated by clinicians in order to more appropriately apply test results to patient care.