Appropriate treatment of pain requires an understanding of the characteristics of pain, including the severity and the nature of the pain-for example, acute versus chronic pain or nociceptive versus neuropathic pain. Appropriate treatment requires an understanding of the efficacies of the available agents in different pain models, and their adverse events, to best match them to the type of pain. While numerous classes of drugs are used to treat pain, 3 categories in particular-acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids-are most often used for the treatment of pain, along with adjuvants (eg, muscle relaxants, anticonvulsants). Each of these drugs is associated with different adverse events and with varying degrees of efficacy. In general, acetaminophen is the least potent, while NSAIDs and opioids offer stronger analgesic effects. At the same time, acetaminophen use can cause acute liver failure, and NSAIDs are associated with serious complications impacting the gastrointestinal, cardiovascular, and renal systems. Opioids can cause cognitive deficiency, motor impairment, and respiratory depression, among other problems; they also represent a significant addiction risk in certain groups of patients. This article reviews the safety and efficacy of NSAIDs relative to other therapeutic agents in the treatment of 4 common types of pain, summarizes clinical treatment guidelines in these types of pain, and compares the relative roles of NSAIDs, acetaminophen, and opioids in treating pain.