Platelet-activating factor (PAF) is a phospholipid mediator with widespread biological actions. PAF acts as both an intercellular and intracellular mediator via activation of plasma membrane and intracellular binding sites, respectively. Pharmacological manipulations - using cell site-specific PAF antagonists - can be used to dissect the site of PAF action. Evidence suggests that PAF is a mediator of inflammatory-based pain; PAF elicits, and PAF antagonists attenuate, the inflammatory nociceptive response. For instance, using the biphasic formalin model in rats, we recently demonstrated that systemic, cerebral, and hippocampal administration of PAF antagonists - selective for either intracellular or plasma membrane PAF receptors - decreased the late-phase of the nociceptive response. Interestingly, the site-selective PAF antagonists may act at distinct anatomical locations to alleviate nociception. Thus, PAF may not only at act at distinct anatatomical sites, but at distinct binding sites within these anatomical locales, to modulate the processing of pain of an inflammatory nature. PAF is known to elicit rapid activation of several protein kinase pathways, and to induce mobilization of prostaglandin E2 (PGE2) release. As these mediators are critical signals in nociception, PAF could be an important early mediator of inflammatory-based pain.