Pain is one of the most common reasons for patients to visit the emergency department. The ever-growing research on emergency department analgesia has challenged the current practices with respect to the optimal analgesic regimen for acute musculoskeletal pain, safe and judicious opioid prescribing, appropriate utilization of non-opioid therapeutics, and non-pharmacological treatment modalities. This clinical review is set to provide evidence-based answers to these challenging questions.