Cardiovascular disorders and acute coronary syndrome represent the leading pathologies in western countries. Over 30 years from the first diagnostic criteria issued by the World Health Organization, the diagnostic approach to patients with non-traumatic chest pain is as yet challenging. Investigators have attempted various diagnostic strategies, such as clinical decision algorithms, cardiac biomarkers, echocardiography, and myocardial perfusion imaging to avoid missing patients with myocardial ischemia or unstable angina. Although the pivotal role of cardiac troponins has now been widely recognized in the clinical management of myocardial ischemia, several patients with acute coronary syndrome might present with nondiagnostic concentrations on admission. The appropriate utilization of economical and therapeutical resources largely depends on early risk stratification, to either rule out or diagnose acute coronary syndromes, and early markers of myocardial ischemia and reliable prognostic indicators should now support investigative strategies. The ischemia-modified albumin and the brain natriuretic peptides have been recently proposed as promising markers for the early stratification of risk and prognosis. If reliable studies will confirm their suitability for evaluating patients presenting with acute coronary syndrome, a novel diagnostic approach might issue.