Meade and Weiss (2007) present a timely review of HIV sexual risk behavior in serious mental illness (SMI) and substance use disorders (SUD), and identify a critical paucity of relevant HIV prevention research. They suggest pathways by which SMI/SUD may combine to create risks for HIV. This commentary suggests that the complexities of this patient population may be better suited to hybrid models (Carroll & Rounsaville, 2003) combining the priorities of efficacy and effectiveness. We consider some recent modifications to cognitive-behavioral therapy (CBT) interventions that may provide useful tools to support HIV prevention. The challenges presented by HIV infection in this group are also considered in relation to our current work adapting traditional CBT to treat mental health and substance use issues in the context of HIV infection and/or prevention.