An opioid crisis has taken hold in North America, unfortunately highlighted by over 47,600 overdose deaths due to opioid use in 2017 in the United States. The trans-National Institute of Health (NIH) initiative called the NIH HEAL (Helping to End Addiction long-term) has two primary therapeutic aims: (1) decreasing opioid-induced overdoses and opioid use disorder (OUD); (2) developing novel non-opioid and non-addictive based therapeutics for the treatment of chronic pain. The special section on the opioid crisis found in The Journal of Pharmacology and Experimental Therapeutics November 2019 (371/2) issue addresses both preclinical and clinical aspects needed for a scientific response to this escalating crisis. All content in the special section is freely accessible through February 1, 2020.