Objective: We sought to determine the diagnostic accuracy of clinical prediction rules to exclude acute coronary syndrome (ACS) in the emergency department (ED) setting. Methods: We searched MEDLINE, EMBASE, Web of Science and the Cochrane Database of Systematic Reviews. We contacted content experts to identify additional articles for review. Reference lists of included studies were hand searched, We selected articles for review based on the following criteria: 1) enrolled consecutive ED patients; 2) incorporated variables from the history or physical examination, electrocardiogram and cardiac biomarkers; 3) did not incorporate cardiac stress testing or coronary angiography into prediction rule; 4) based on original research; 5) prospectively derived or validated; 6) did not require use of a computer; and 7) reported sufficient data to construct a 2 ∞ 2 contingency table. We assessed study quality and extracted data independently and in duplicate using a standardized data extraction form. Results: Eight studies met inclusion criteria, encompassing 7937 patients. None of the studies verified the prediction rule with a reference standard on all or a random sample of patients. Six studies did not report blinding prediction rule assessors to reference standard results, and vice versa. Three prediction rules were prospectively validated. Sensitivities and specificities ranged from 94% to 100% and 13% to 57%, and positive and negative likelihood ratios from 1.1 to 2.2 and 0.01 to 0.17, respectively. Conclusion: Current prediction rules for ACS have substantial methodological limitations and have not been successfully implemented in the clinical setting. Future methodologically sound studies are needed to guide clinical practice.