Understanding the ability of drugs of abuse to impair many aspects of the immune system has become more urgent as it has aroused serious global problems of considerable concern to health. Illicit drugs such as methamphetamine, a highly addictive psychostimulant, alter immune function and increase host susceptibility to infections. Considering the high prevalence and incidence of methamphetamine abuse and its association with HIV-1 infection, understanding the causal mechanisms of how methamphetamine modulates immune function are timely and of paramount importance. Current research is underway to determine how methamphetamine disarms the adaptive immune system, rendering the host more susceptible to HIV-1 infection. Employing a combination of in vitro systems and a well-defined animal model to study the combined effects of HIV-1 and methamphetamine, we are investigating the implications of methamphetamine exposure on T cell functions, underlying mechanism of impaired T cell function and how subsequent T cell dysfunction affects the immune system responses to HIV-1 infection in and outside of CNS. Identification of such underlying mechanisms will highlight new therapeutic and prophylactic methods to improve the immunity in the setting of drug abuse.