The initial evaluation of chest pain in the emergency department is based on the patient's clinical history, changes in the ECG and necrosis biomarkers. Although management of patients with ST-elevation myocardial infarction or non-ST-elevation myocardial infarction with positive markers of myocardial damage is well defined, exclusion of coronary artery disease or myocardial ischemia in the remaining patients is more challenging. This group represents the majority of patients admitted for chest pain syndromes and that have a substantial risk of an adverse outcome. Given that troponin, as a marker of myocardial damage, detects terminal events in the cascade of acute coronary syndrome, there is a need to search for biomarkers that are able to identify patients at high risk, allowing rapid, bedside stratification. Data suggest that clinical events are prone to occur more frequently in patients with coronary artery stenosis associated with myocardial ischemia. Accordingly, identification of systemic biomarkers of ischemia could facilitate identification of high-risk patients with a high burden of coronary atherosclerosis and plaque rupture. We describe six biomarkers that have been linked to myocardial ischemia. Until now, these biomarkers of ischemia are relevant in order to exclude ischemic heart disease (high negative predictive value) but still lack specificity. Future prospective studies should be performed in larger and more diverse sets of patients presenting with ischemia, and in a complementary fashion in order to provide valuable tools for clinical decision making.