Persons who use and abuse drugs are at risk for multiple morbidities that involve addiction, bloodborne infectious diseases, and sexually transmitted diseases, in addition to psychiatric illness and social instability. Infectious diseases acquired as a result of drug use can diffuse into non-drug using populations through other high-risk behaviors. Drug users also have substantial comorbidities from noncommunicable diseases and complications that can affect virtually every organ system in the body. Diagnosis of comorbidities and complications associated with drug abuse usually occurs late in the disease course, particularly for persons who are disenfranchised and have limited or no access to medical care. Medical management of these comorbid conditions constitutes a significant challenge. Directly observed therapy (DOT) can be useful but needs to conform to the needs of the targeted treatment population for full efficacy. DOT may have its greatest impact with drug users destabilized by cocaine or methamphetamine use but has yet to be fully investigated in this patient population.