The history of harm reduction in the USA has led to the development of some of the most important methods for treating persons for drug use disorders, such as methadone and buprenorphine for opiate use disorder. However, there has been fierce political resistance to implementation and scale-up of harm reduction in the USA. This resistance is rooted in historical demonization of particular psychoactive drugs that were associated with stigmatized racial/ethnic groups.With the discovery of acquired immunodeficiency syndrome (AIDS) in 1981, harm reduction became important not only for treating substance use disorders, but for reducing transmission of blood-borne infection. However, within the context of the crack cocaine epidemic in the 1980s, it was very difficult to implement any programs that appeared to "condone" drug use.It was not until the late 1980s that syringe exchange programs began at the state and local level in the USA. With funding primarily from state and local governments and the support of the North American Syringe Exchange Network (NASEN), there are now approximately 200 programs for syringe exchange in the USA. Research has shown that these programs have been extremely effective in reducing human immunodeficiency virus (HIV) transmission among persons who inject drugs (PWID). The programs in the USA also offer many additional services for drug users, including condom distribution, referrals to substance abuse treatment, HIV, hepatitis C virus (HCV), hepatitis B virus (HBV) counseling and testing, overdose education and naloxone distribution to reverse for overdose.Currently, the USA is experiencing an opioid/heroin epidemic, with significant increases in overdose deaths among drug users. Much of this epidemic is occurring in suburban and rural of the country without harm reduction services. The current challenges for harm reduction and harm reduction research involve expansion of services to suburban and rural areas and implementation science on how to effectively and efficiently address HCV transmission and overdose. Most importantly, continued research efforts are needed to reduce the stigma of psychoactive drug use. While political opposition continues, harm reduction activists and researchers have developed a highly effective partnership based on a common core values.