Despite important advancements in acute myocardial infarction (AMI) management, it continues to represent a leading cause of mortality worldwide. Fast and reliable AMI diagnosis can significantly reduce mortality in this high-risk population. Diagnosis of AMI has relied on biomarker evaluation for more than 50 years. The upturn of high-sensitivity cardiac troponin testing provided extremely sensitive means to detect cardiac myocyte necrosis, but this increased sensitivity came at the cost of a

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... ecrease in diagnostic specificity. In addition, although cardiac troponins increase relatively early after the onset of AMI, they still leave a time gap between the onset of myocardial ischemia and our ability to detect it, thus precluding very early management of AMI. Newer biomarkers detected in processes such as inflammation, neurohormonal activation, or myocardial stress occur much earlier than myocyte necrosis and the diagnostic rise of cardiac troponins, allowing us to expand biomarker research in these areas. Increased understanding of the complex AMI pathophysiology has spurred the search of new biomarkers that could overcome these shortcomings, whereas multi-omic and multi-biomarker approaches promise to be game changers in AMI biomarker assessment. In this review, we discuss the evolution, current application, and emerging blood biomarkers for the diagnosis of AMI; we address their advantages and promises to improve patient care, as well as their challenges, limitations, and technical and diagnostic pitfalls. Questions that remain to be answered and hotspots for future research are also emphasized.