Abstract For many years, cellular assays, including mixed leukocyte reactions, cell-mediated lympholysis, and T helper and T cytotoxic cell precursor frequency analyses, have been used to monitor the immune response status of organ allograft recipients. The predictive value, sensitivity, and specificity of such assays have often been questioned. In addition, no in vitro assay has been shown to correlate reliably with or to predict operational tolerance. As tolerogenic strategies are introduced into clinical testing, the need for development and validation of “tolerance” assays is great. Herein, we survey contemporary and emerging technologic approaches to confront this challenge.