The need to alleviate pain is among the first recorded uses for medicines, dating back to the onset of the Neolithic period. The need persists and many of today's best-known drugs (e.g. aspirin, acetaminophen, morphine) are included within this category. An analysis of FDA-approved new molecular entities (NMEs) for pain and anesthesia reveals a fluctuating rate of new introductions, which has plummeted in recent years. The largest emphasis has been placed on acute pain, largely targeting G-protein-coupled receptors and a relatively narrow subset of molecular pathways. NMEs targeting anesthesia tend to focus on channels and four molecular pathways capture a large majority of NMEs for this indication.