Few diagnostic decisions in medicine have been more heavily researched and debated than the approach to patients with acute chest pain. In addition, the question is which patients with acute chest pain have a presentation benign enough to make discharge from the emergency department safe and appropriate despite the advances in diagnostic tests. There is always the possibility of missed diagnosis which may cause substantial morbidity and mortality. The use of algorithms or protocols is not always sufficient to avoid missed diagnosis and the individual physicians's diagnostic performance and clinical experience is as important as the best algorithm for atypical chest pain! Patients with atypical symptoms are most likely to be mistakenly discharged. This article does mainly focus on diagnostic tests including ECG and biomarkers such as troponin and D-dimer as well as the investigation by helical CT scan in patients with suspected pulmonary embolism. The article also discuss the importance of repeated assessments of biomarkers and the determination of the exact time interval between the first clinical symptoms and the presentation to the emergency department. This time interval can be very crucial for the diagnostic work-up of patients with acute chest pain.