Cardiac myosin binding protein-C (cMyBP-C) regulates sarcomeric structure, as well as myocardial contractility, and its phosphorylation is known to confer cardioprotection. We recently showed that cMyBP-C is an easily releasable and soluble myofilament; dephosphorylation of cMyBP-C results in its degradation and release into the blood post-myocardial infarction (MI); and plasma cMyBP-C levels are significantly increased in animal models and patients with MI. Strikingly, the level of plasma cMyBP-C is significantly (twofold) higher than the gold-standard plasma cardiac troponin-I (cTnI). This editorial provides an opportunity to discuss cMyBP-C as a potential new biomarker signaling ischemia-reperfusion injury. It is, however, clear that defining cMyBP-C as a bona fide selective and cardiac-specific biomarker of ischemia-reperfusion injury, as well as validating precise plasma cMyBP-C levels, will require further studies using systematic and advanced proteomics methods. Acute coronary syndrome (ACS) encompasses all conditions that are caused by a sudden inadequate perfusion of the heart. This can occur through a decrease of blood flow or increased demand to the heart. ACS includes ST-segment elevation MI (STEMI), non-STEMI (NSTEMI) and unstable angina [1]. Symptoms can vary from classic crushing chest pain that radiates down the left arm to non-descript jaw or back sensations. Every 25 s, approximately one American will experience ACS with an estimated 34% chance of dying within 1 year subsequent to the ACS event [1]. An ECG provides immediate diagnosis of STEMI, activating a fast 90-min treatment pathway from first medical contact to opening the blocked coronary artery (i.e., ‘door to balloon time’) [2]. However, ST-elevation could be due to other causes such as pericarditis, early repolarization and ventricular hypertrophy. More importantly, life-threatening NSTEMI/unstable angina can still be missed due to a nondiagnostic ECG. Furthermore, the incidence of NSTEMI has increased (from 126 to 132 per 100,000), while the incidence of STEMI has decreased (from 121 to 77 per 100,000) between 1997 and 2005 [3]. Moreover, NSTEMI shows greater 1-year mortality (18.7–27.6%) than STEMI (8.3–15.4%) [3]. When a patient presents with ACS, but without ST-segment elevation, a clinician has to decide on either an early invasive or conservative approach based on assessment of the patient’s risk [4,5]. Currently, this decision process can be difficult. The Timing of Intervention in Patients with Acute Coronary Syndromes (TIMACS) trial has shown that early invasive therapy decreases the possibility of death, MI and stroke in higher risk NSTEMI/unstable angina patients compared with standard care, with longer time to invasive therapy [6]. The American Heart Association (AHA) guidelines [4,5], the Global Registry of Acute Coronary Events (GRACE) score [4] and the Thrombolysis in Myocardial Infarction (TIMI) risk score [4] all require a positive circulatory biomarker as an indicator of high risk of heart attack. Consequently, biomarkers play a crucial role in risk-stratifying a NSTEMI ACS patient for proper care [4,5]. In this time-critical context, cMyBP-C has the potential to outperform cardiac troponins at identifying patients needing early invasive therapy and can be used to diagnose recurrent MI, which is not possible with troponins as they cannot diagnose delayed clearance.