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Allograft rejection remains a significant concern after all solid organ transplants. Although qualitative morphologic analysis with histologic grading of biopsy samples is the main tool employed for diagnosing allograft rejection, this standard has significant limitations in precision and accuracy that affect patient care. The use of endomyocardial biopsy to diagnose cardiac allograft rejection illustrates the significant shortcomings of current approaches for diagnosing allograft rejection. Despite disappointing interobserver variability, concerns about discordance with clinical trajectories, attempts at revising the histologic criteria and efforts to establish new diagnostic tools with imaging and gene expression profiling, no method has yet supplanted endomyocardial biopsy as the diagnostic gold standard. In this context, automated approaches to complex data analysis problems—often referred to as “machine learning”—represent promising strategies to improve overall diagnostic accuracy. By focusing on cardiac allograft rejection, where tissue sampling is relatively frequent, this review highlights the limitations of the current approach to diagnosing allograft rejection, introduces the basic methodology behind machine learning and automated image feature detection, and highlights the initial successes of these approaches within cardiovascular medicine.