Men who have sex with men (MSM) remain disproportionately infected with HIV. MSM accounted for 53% of the 56,300 new HIV infections in the US in 2006, despite representing only 4% of the national male population [1, 2]. This high HIV disease burden coincides with high prevalence of non-injection substance use and alcohol consumption among US MSM. A national MSM sample found a 42% previous year prevalence for any non-injection substance use [3]. The recently released United States National HIV/AIDS strategy highlights the need to address substance use among MSM as a critical component of reducing HIV incidence in the United States [4]. To advance this goal, it is imperative to: (1) redress the knowledge gaps on patterns of non-injection substance use among substance using MSM (SUMSM); (2) improve upon existing interventions; (3) develop effective, scalable interventions for the spectrum of users; and (4) determine how to best identify and address the structural and cultural factors that may contribute to non-injection substance use in the MSM population. Non-injection substance use may increase susceptibility to HIV infection in multiple ways [5, 6]. Many epidemiological studies document the association between these substances and sexual risk behaviors [7–24]. These sexual risks are paralleled by high rates of incident and prevalent HIV cases and sexually transmitted infections among SUMSM. Most notably, methamphetamine, cocaine, poppers, and alcohol use have each been associated with an increased risk for HIV and other STD infections [9, 12, 24–30]. The contribution of polysubstance use may also be considerable [9, 28, 31]. Patterns of Substance Use among MSM Drug use among MSM is not an all or nothing phenomenon. There needs to be more emphasis on addressing the specific patterns of non-injection substance use among SUMSM, and what implications these patterns have for intervention approaches. Most SUMSM are not drug-dependent, but rather use episodically (i.e., using substances less than weekly). National HIV Behavioral Surveillance (NHBS) data show that 69–86% of SUMSM report less than weekly substance use [32–35]. Episodic binge drinking is also common among high-risk MSM [36, 37]. Importantly, episodic patterns are associated with high-risk sexual behaviors, suggesting that while perhaps less concerning from a drug-dependence perspective, they may nonetheless contribute substantially to HIV transmission rates among SUMSM [24, 38]. Polysubstance use patterns (i.e., taking more than one substance concurrently, or periodically over a period of time) are often the norm among SUMSM. For example, exclusive of alcohol use, 93% of non-injection methamphetamine using MSM in the San Francisco NHBS sample reported polysubstance use during the prior 12 months before interview; similarly, 94% of cocaine and 90% of poppers users reported using other substances [39]. In a sample of HIV-positive methamphetamine using MSM, 95% of respondents were polysubstance users [40]. Similar findings were reported among samples of MSM club drug users and African American MSM [41–43]. Among various MSM samples, 11–44% of participants reported recent use of three or more substances [44–48]. We need to better understand how to address the wide spectrum of non-injection substance use patterns among MSM. At one extreme are the substance-dependent MSM for whom risk behavior and substance use morbidity may be especially high. Yet, there is also the larger population of MSM whose substance use is infrequent, but for whom it is associated with harmful use and HIV risk. It is unclear where on the substance use spectrum interventions should be invested to have the maximum effectiveness. There is also little understanding as to why, with overall substance use being so prevalent among MSM, only a small proportion develops dependence. Similarly, there is a paucity of understanding as to why some MSM do not use substances, and what factors confer protective effects or relative resiliency with regard to substance use [49]. Finally, how substance use patterns vary across the life trajectories of MSM and how those variations coincide with major life milestones (e.g., sexual debut, coming out, dating, aging, etc.), remains largely unexplored.