Crossmatching of potential renal donors against potential renal transplant recipients has been performed for over 40 years and is a mandatory component of the transplant work-up process. However, gone are the days when all that was available was the T-cell complement-dependent cytotoxicity crossmatch. There are now many more options available for determining the likelihood of donor-specific antibody-mediated responses including flow crossmatching and the virtual crossmatch. In addition, assays to determine the extent of sensitization of cell-mediated responses are being examined. This article builds an understanding of modern day crossmatch interpretation using a case-based approach in order to provide a framework for the general nephrologist to determine the likely immune consequences of a particular donor-recipient pairing.