The approach to patients with acute pain begins by identifying the underlying cause and a disease-specific treatment. The first-line pharmacologic agent for the symptomatic treatment of mild to moderate pain is acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). The choice between these two medications depends on the type of pain and patient risk factors for NSAID-related adverse effects (e.g., gastrointestinal, renovascular, or cardiovascular effects). Different NSAIDs have similar analgesic effects. However, cyclooxygenase-2 selective NSAIDs (e.g., celecoxib) must be used with caution in patients with cardiovascular risk factors and are more expensive than nonselective NSAIDs. If these first-line agents are not sufficient for mild to moderate pain, medications that target separate pathways simultaneously, such as an acetaminophen/opioid combination, are reasonable choices. Severe acute pain is typically treated with potent opioids. At each step, adjuvant medications directed at the underlying condition can be used. Newer medications with dual actions (e.g., tapentadol) are also an option. There is little evidence that one opioid is superior for pain control, but there are some pharmacologic differences among opioids. Because of the growing misuse and diversion of controlled substances, caution should be used when prescribing opioids, even for short-term treatment. Patients should be advised to properly dispose of unused medications.