Although the use of low-molecular-weight heparins for treatment of acute coronary syndromes (ACS) has increased in recent years, unfractionated heparin (UFH) remains the drug of choice for many patients and institutions. One reason is that this agent is safe for patients with renal dysfunction as well as those who undergo percutaneous coronary intervention or coronary artery bypass graft. The use of UFH is complicated by the increased risk of bleeding due to concurrent administration of numerous antiplatelet drugs in most patients with ACS, the limited data regarding ideal therapeutic range, and the wide variability of patient response. Knowledge regarding the optimal therapeutic range and how to achieve it efficiently may enable clinicians to improve clinical outcomes in patients with ACS. We reviewed and analyzed the available evidence to clarify how to best manage UFH therapy in patients with ACS. Current data support the use of a lower and narrower therapeutic range for patients with ACS than the range that is used for venous thromboembolism. Many factors in addition to weight affect patient response to UFH, including age, sex, diabetes mellitus, smoking status, and obesity.