The best and safest treatment for pain is with topical treatments on the skin. This is most evident with acupuncture that occurs in the skin, is safe and effective. Even broken bones, post-operative pain, replaced hips, replaced knees, cancer pain and other severe pain can be treated effectively and safely with topical medicines. A liniment is available that has been used in many acute and chronic pain patients with success as will be discussed. Cyclooxygenase-2 is found in the skin and is induced in chronic pain conditions. Oral medications do not reach high enough concentrations in the skin to inhibit the enzyme. Instead, oral nonsteroidal anti-inflammatory medications poison the body and are toxic to the stomach and kidneys. These oral medications cause at least 10,000 ulcer deaths yearly in the USA. They also cause clotting problems that lead to heart attacks and strokes. Pain is sensed in the skin at sensory afferent neurons. The activities of pain sensing transient receptor potential cation channels in these neurons are increased by prostaglandins made by cyclooxygenase-2. Pain is best treated with topical preparations that penetrate the skin in small amounts, inhibit cyclooxygenase-2 and are not poisonous to the body. Sesquiterpenes are 15 carbon compounds found in plants and can penetrate the skin. These compounds down regulate the transcription of cyclooxygenase-2 through an NF-kB mediated mechanism and may also inhibit cyclooxygenase-2 and other targets directly. This review is a discussion of the medicinal chemistry and pharmacology of sesquiterpenes that permits these molecules to relieve severe and chronic pain.