Summary:  High throughput, high density platforms for transcriptional, proteomic, and metabonomic analyses are opening new doors for improving our understanding of the complexity and redundancy of the immune system in the interplay of the innate and allo-immune responses in organ transplantation. New insights are being obtained into the possible discrepancies between the gold standard of tissue pathological diagnosis and clinical graft outcomes, as new transcriptional categories of transplant rejection evolve. The bystander effects of chronic immunosuppression underlying the complexities of graft dysfunction are beginning to be understood. Non-invasive mechanisms to monitor transplants, by following ‘footprints’ of biomarker sets that reflect the disease phenotype, are being pursued for their clinical application for direct patient care. Utilization of these same biomarker sets may also offer a unique means to titrate immunosuppression and predict specific graft dysfunction events prior to clinical decline, thus bringing in the potential to reduce patient morbidity from infection and malignancy, preserve graft integrity, and limit the progression of chronic graft injury. Bioinformatics support is integral to the unraveling of the mysteries of the human genome, proteome, and metabolome in disease and in health.