The past few decades are characterized by an explosive evolution of genetics and molecular cell biology. Advances in chemistry and engineering have enabled increased data throughput, permitting the study of complete sets of molecules with increasing speed and accuracy using techniques such as genomics, transcriptomics, proteomics, and metabolomics. Prediction of long-term outcomes in transplantation is hampered by the absence of sufficiently robust biomarkers and a lack of adequate insight into the mechanisms of acute and chronic alloimmune injury and the adaptive mechanisms of immunological quiescence that may support transplantation tolerance. Here, we discuss some of the great opportunities that molecular diagnostic tools have to offer both basic scientists and translational researchers for bench-to-bedside clinical application in transplantation medicine, with special focus on genomics and genome-wide association studies, epigenetics (DNA methylation and histone modifications), gene expression studies and transcriptomics (including microRNA and small interfering RNA studies), proteomics and peptidomics, antibodyomics, metabolomics, chemical genomics and functional imaging with nanoparticles. We address the challenges and opportunities associated with the newer high-throughput sequencing technologies, especially in the field of bioinformatics and biostatistics, and demonstrate the importance of integrative approaches. Although this Review focuses on transplantation research and clinical transplantation, the concepts addressed are valid for all translational research.