The term “single-sample rule-out” refers to the ability of very low concentrations of high-sensitivity cardiac troponin (hs-cTn) on presentation to exclude acute myocardial infarction with high clinical sensitivity and negative predictive value. Observational and randomized studies have confirmed this ability. Some guidelines endorse use of a concentration of hs-cTn at the assay’s limit of detection, while other studies have validated the use of higher concentrations, allowing this approach to identify a greater proportion of patients at low risk. In most studies, at least 30% of patients can be triaged with this approach. The concentration of hs-cTn varies according to the assay used and sometimes how regulations permit reporting. It is clear that patients need to be at least 2 hours from the onset of symptoms being evaluated. Caution is warranted, particularly with older patients, women, and patients with underlying cardiac comorbidities.