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Although decades of the reductionist approach achieved great milestones in optimizing the immunosuppres-sion therapy, traditional clinical parameters still fail in predicting both acute and chronic (mainly) rejection events leading to higher rates across all solid organ transplants. To clarify the underlying immune-related cel-lular and molecular mechanisms, current biomedical research is increasingly focusing on "transplantomics" which relies on a huge quantity of big data deriving from genomics, transcriptomics, epigenomics, proteomics, and metabolomics platforms. The AlloMap (gene expression) and the AlloSure (donor-derived cell-free DNA) tests represent two successful examples of how omics and liquid biopsy can really improve the precision med-icine of heart and kidney transplantation. One of the major challenges in translating big data in clinically useful biomarkers is the integration and interpretation of the different layers of omics datasets. Network Medicine offers advanced bioinformatic-molecular strategies which were widely used to integrate large omics datasets and clinical information in end-stage patients to prioritize potential biomarkers and drug targets. The applica-tion of network-oriented approaches to clarify the complex nature of graft rejection is still in its infancy. Here, we briefly discuss the real-life clinical applications derived from omics datasets as well as novel opportunities for establishing predictive tests in solid organ transplantation. Also, we provide an original "graft rejection interactome" and propose network-oriented strategies which can be useful to improve precision medicine of solid organ transplantation.