Well-documented as a botanical medicine for over 5000 years, the discovery of endogenous cannabinoid receptors and evidence-based reports indicating the efficacy of medical cannabis for treating pain have renewed consideration of its therapeutic use. The chapter emphasizes how appreciating the biologic context of how and why endogenous cannabinoid receptors function will allow healthcare providers to better interpret pre-clinical trials and limited evidence-based data. Examination of the cannabis plant’s biochemistry and mechanisms of action has revealed so-called endocannabinoid receptors and their natural ligands, comprising a previously unknown ubiquitous receptor system responsible for maintaining physiological balances that are essential to sustain animal life. In consideration of opioids and balanced risk reduction strategies, this chapter summarizes evidence-based safety and efficacy profiles that suggest therapeutic balances of phytocannabinoid and terpenoid compounds. The conclusion discusses a bioethical rationale for compassionate access to cannabis when used for the treatment of pain as well as public health concerns from contaminants to dependence.