Current practice in the monitoring of cardiac transplants revolves around the use of the endomyocardial biopsy. While this is effective for the identification of an ongoing immune response in the graft, for years investigators have explored less invasive approaches in the hope of achieving the same goal by examining the patient's immune response. For a number of years, lymphocytes, their subsets, and their level of activation in the periphery were investigated. To a large degree, it was a lack of specificity in these approaches that led to their falling out of favor. Examination of donor-specific reactivity by means of lymphocyte proliferation assays has also been used; however, these approaches have been impeded by the time and effort required to accomplish them. During the last few years, flow cytometric cross-matching during the posttransplant period has been used at our institution. While this cross-matching focuses on the humoral immune responses, we have found it to be of value in identifying patients at risk of rejection and in allowing the assessment of treatment modalities used to treat ongoing rejection. While the perfect approach remains to be found, the potential advantages of immunologic monitoring would seem to justify continued study.