Acute compartment syndrome (ACS) is an infrequent but true medical emergency caused by an increase in pressure in noncompliant tissue compartments resulting in decreased blood flow, ischemia, and tissue necrosis. At present, it is mainly a clinical diagnosis of pain “out of proportion” to the clinical scenario. Other signs such as paresthesia, paralysis, and the lack of peripheral pulses are, usually, late symptoms. Early diagnosis and treatment can be the difference between preserving function of the affected extremity, permanent functional loss, or even amputation. Regional anesthesia and analgesia are controversial in patients at risk for compartment syndrome due to potential masking of ischemic pain associated with ACS. A recent and growing body of anecdotal case reports and research evidence, however, suggests that ischemic pain pathways are complex and may differ from those of nociceptive or neuropathic pain. That is, ischemic pain most likely has a sympathetic pathway that cannot be completely blocked by peripheral nerve blocks. This article explores the possible role and controversies surrounding the use of regional anesthesia, continuous peripheral nerve blocks, and analgesia in patients at risk of developing ACS.