Cannabis use is increasing among some demographics in the United States and is tightly linked to anxiety, trauma, and stress reactivity at the epidemiological and biological level. Stress-coping motives are highly cited reasons for cannabis use. However, with increased cannabis use comes the increased susceptibility for cannabis use disorder (CUD). Indeed, CUD is highly comorbid with posttraumatic stress disorder (PTSD). Importantly, endogenous cannabinoid signaling systems play a key role in the regulation of stress reactivity and anxiety regulation, and preclinical data suggest deficiencies in this signaling system could contribute to the development of stress-related psychopathology. Furthermore, endocannabinoid deficiency states, either pre-existing or induced by trauma exposure, could provide explanatory insights into the high rates of comorbid cannabis use in patients with PTSD. Here we review clinical and preclinical literature related to the cannabis use-PTSD comorbidity, the role of endocannabinoids in the regulation of stress reactivity, and potential therapeutic implications of recent work in this area.