Abstract The transient receptor potential vanilloid type 1 channel (TRPV1; originally vanilloid receptor VR1) is activated in peripheral terminals of nociceptive fibers by noxious heat, low pH, and natural products such as capsaicin, the pungent ingredient of red-hot chilli peppers. Evidence has been accumulating that TRPV1 is expressed also in the brain, where it seems to be involved in antinociception, locomotor control, and regulation of affective behaviors. This ion channel might be activated by arachidonoyl ethanolamide (anandamide), the endogenous agonist of the cannabinoid type 1 (CB1 ) receptor. However, while CB1 activation leads to a decrease in intracellular calcium and attenuation of synaptic transmission, anandamide binding to TRPV1 results in elevated calcium levels and potentiated synaptic transmission. This suggests a tripartite regulatory system with antagonistic effects of CB1 and TRPV1, which are tied together by the same endogenous ligand. Such a system may have important implication for the modulation of behavioral responses. The present commentary elaborates on this interplay between CB1 receptors and TRPV1 channels in the context of fear- and anxiety-related behaviors. This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.