Despite important progress in recent decades, mortality remains high for patients with chronic heart failure. Risk stratification may be refined by the use of biomarkers for different pathophysiological processes that established mortality risk factors do not directly reflect. Biomarkers that are currently available can provide information about at least 7 pathobiological processes operative in HF, help to identify the specific processes involved in individual patients, and aid in constructing management plans. However, the additional prognostic information gained by any biomarker over a clinical risk model plus other biomarkers needs to be determined with adequate statistical tools. A major problem in selecting a biomarker profile is the proportional increase in economic burden; thus, the addition of any biomarker to a profile should be justified by adequate discrimination, calibration, reclassification, and likelihood analyses. Three studies that implemented such rigorous analyses have assessed a multimarker panel in chronic heart failure that incorporated the biomarker ST2: the Penn HF Study, the Barcelona Study, and the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) biomarker substudy. In all 3 studies, a multimarker panel appeared to provide significant information over conventional risk stratification. The latter 2 reports proposed that ST2 might be superior to natriuretic peptides. The Barcelona Bio-HF calculator (www.bcnbiohfcalculator.cat) is a novel risk calculator that considers clinical variables, treatment, and biomarkers (i.e., N terminal pro-brain natriuretic peptide [NT-proBNP], ST2, and high sensitivity troponin T [hsTnT]). The optimal panel of markers, the change in these markers over time, and how these changes might help guide therapeutic interventions remain to be defined.