Palmitoylethanolamide (PEA) is a bioactive fatty acid amide belonging to the class of N-acyl-ethanolamines (NAEs). This compound has been known since the 1950s for its anti-inflammatory effects, but was re-discovered only after the finding that another NAE, arachidonoyl-ethanolamide (anandamide, AEA), could act as an endogenous ligand of cannabinoid receptors. Although a similar function for PEA has also been proposed, this compound does not activate the two cannabinoid receptor subtypes described to date. PEA and AEA are co-synthesized by cells, and PEA might act as an ‘entourage’ compound for AEA, i.e. as an endogenous enhancer of AEA biological actions. Indeed, long-term treatment of human breast cancer cells (HBCCs) with PEA downregulates the expression of the enzyme responsible for AEA degradation, the fatty acid amide hydrolase, thereby leading to an enhancement of AEA-induced, and cannabinoid CB1 receptor-mediated, cytostatic effect on HBCCs. AEA is also a full agonist for the receptors of another class of bioactive fatty acid amides, the N-acyl-vanillyl-amines (e.g. capsaicin and olvanil). These sites of action are known as vanilloid receptors of type 1 (VR1). PEA enhances the VR1-mediated effects of AEA and capsaicin on calcium influx into cells. These ‘entourage’ effects of PEA might be attributable to modulation of VR1 activity, and could underlie the enhancement by PEA, described here for the first time, of the antiproliferative effects of VR1 receptor agonists.