The monitoring of transplanted hearts is currently based on histological evaluation of endomyocardial biopsies, a method that is fairly insensitive and that does not always accurately discriminate between rejection and infection in the heart. Accurate diagnosis of rejection and infection is absolutely crucial, however, as the respective treatments are completely different. Using microarrays, we analyzed gene expression in 76 cardiac biopsies from 40 heart recipients undergoing rejection, no rejection, or Trypanosoma cruzi infection. We found a set of genes whose expression patterns were typical of acute rejection, and another set of genes that discriminated between rejection and T cruzi infection. These sets revealed acute rejection episodes up to 2 weeks earlier, and trypanosome infection up to 2 months earlier than did histological evaluation. When applied to raw data from other institutions, the 2 sets of predictive genes were also able to accurately pinpoint acute rejection of lung and kidney transplants, as well as bacterial infections in kidneys. In addition to their usefulness as diagnostic tools, the data suggest that there are similarities in the biology of the processes involved in rejection of different grafts and also in the tissue responses to pathogens as diverse as bacteria and protozoa.