•We highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications.•Amplifying eCBs by attenuating eCB-degradation, via fatty acid amide hydrolyze or monoacylglycerol lipase, reduces anxiety.•A non-canonical route to regulate eCB degradation and anxiety involves interfering with cyclooxygenase-2 (COX-2).•Anxiety can be affected by targeting the CB2R subtype and the transient receptor potential vanilloid receptor type 1 (TRPV1).•Cannabidiol (CBD) represents another plausible path to modulating eCBs to alleviate anxiety. The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.