Despite nearing the end of the decade of pain research, the analgesic mechanisms of one of the most widely used and popular analgesics remains uncertain. Acetaminophen (APAP) (paracetamol [PARA]) has been used clinically for over a half of a century and although clinicians seem to be comfortable with its benefits, risks, and limitations, they still remain in the dark as to precisely what is providing its pain relief. What does seem clearer is that the predominant mechanisms of APAP's analgesic effects are in the central nervous system (CNS). Although, which central effects are largely responsible for APAP's effects on pain continue to be uncertain. Perhaps, the most accepted theory is that of APAP's positive effects on the serotonergic descending inhibitory pathways. However, interactions with opioidergic systems, eicosanoid systems, and/or nitric oxide containing pathways may be involved as well. Furthermore, endocannabinoid signaling may play a role in APAP's activation of the serotonergic descending inhibitory pathways. A greater understanding of APAP's analgesic mechanisms may promote optimal utilization of analgesic polypharmacy.