Acetaminophen is a popular, universally used, over-the-counter pain medication contained in more than 600 different products and available in a plethora of dosage forms. Acetaminophen is an important adjunct to manage postoperative dental pain in combination with a nonsteroidal anti-inflammatory drug such as ibuprofen. For the treatment of more severe pain, acetaminophen is often formulated with non-opioid and opioid agents. Because of the accessibility of acetaminophen and its widespread use, dental practitioners need to be cognizant of any significant safety concerns that may be associated with this drug, including acetaminophen toxicity. This article discusses the history of acetaminophen, its pharmacology, metabolism, and toxicity, as well as strategies to help address some of the potential safety issues with this medication, including unintentional overdosing.