Club drugs such as methylenedioxymethamphetamine (MDMA, ecstasy), gamma hydroxybutyrate (GHB), and ketamine are among the fastest-growing drugs of abuse in the United States. Reports have shown that some gay and bisexual men are likely to engage in club-drug use in a myriad of venues. This is concerning given that the use of club drugs has been linked to high-risk sexual behaviors. Further, the use of club drugs by HIV-seropositive individuals may have detrimental outcomes on disease progression by either influencing adherence, resulting in drug-drug interactions with antiretrovirals, or potentially compounding immune suppression. Clinicians caring for HIV-seropositive and -seronegative individuals should be aware of the clinical effects and management guidelines associated with these chemicals. This article reviews the available literature with regard to the use of club drugs by HIV-seropositive and -seronegative gay and bisexual men. Although club-drug use may be associated with many risk behaviors for HIV infection, this review focuses on risk behavior among gay and bisexual men since this is the group for which the most data have been reported. The clinical effects and management guidelines associated with these agents are described, and the potential detrimental effects of these substances on HIV disease are discussed.