Controversy is associated with the issue of cannabis and cannabinoids in clinical care in the United States. Recent research has demonstrated the underlying mechanisms of cannabinoid analgesia via endocannabinoids, an endogenous system of retrograde neuromodulatory messengers that work in tandem with endogenous opioids. Additional receptor and non-receptor mechanisms of cannabinoid drugs have pertinent activity, including anti-carcinogenesis and neuroprotection, that may be of key importance in aging and terminal patient populations. The results of clinical trials with synthetic and plant-based cannabinoids suggest that the role of formulation and delivery system is critical in optimizing the risk-benefit profile of cannabinoid products. Synergy between opioids and cannabinoids may produce opioid-sparing effects, as well as extend the duration of analgesia and reduce opioid tolerance and dependence. This article reviews the mechanism of action of cannabinoids, examines marketed agents and those in clinical trials, and addresses their role in treatment of chronic pain, cancer, neurodegenerative diseases, and HIV/ AIDS. The ability of cannabinoid medicines to treat pain, associated sleep disorders, appetite loss, muscle spasm and a wide variety of other symptoms suggests that such agents may in the future play an important role in palliative care.