Patients with non-ST-elevation acute coronary syndromes (ACS) are typically grouped together and treated with similar approaches to therapy despite tremendous variability in clinical presentation and prognosis. The cardiac troponins are biomarkers of myocardial necrosis that have recently been evaluated in conjunction with markers of neurohormonal activation such as brain natriuretic peptide, and markers of systemic inflammation such as C-reactive protein, to further characterize risk in the individual patient presenting with ACS. Measurement of biomarkers that reflect different components of the underlying pathophysiology appears to provide independent and complementary risk stratification information in patients with non-ST-elevation ACS. This review summarizes the rationale for a multimarker approach to risk stratification in ACS and also discusses other cardiac biomarkers under active investigation. One of these of particular interest is soluble CD40 ligand, a biomarker that may not only indicate active inflammation and platelet activation associated with ACS, but may also exhibit direct prothrombotic properties that mediate early atherogenesis, plaque rupture, and thrombosis.