Sexual minority youth are at increased risk of substance use compared to their heterosexual peers, and bisexual youth appear to be at greatest risk. However, little is known about their motivations for and against using substances, how they make decisions, and what consequences they experience. We used qualitative data from a study of 54 cisgender and transgender male youth (ages 14–17 years) who reported attractions to more than one gender or regardless of gender (i.e., bisexual, pansexual, or queer; collectively referred to as bi+) to explore these aspects of substance use. Participants completed a survey and an interview, and interviews were thematically analyzed. Qualitative analyses revealed that participants described diverse motivations for using substances (e.g., to cope with stress, to experiment, to have fun) and for not using them (e.g., concern about consequences, not having access). The most common sources of stress were mental health problems, school, and family. They did not describe sexual orientation-related stress as a motivation for their use, but they acknowledged that it could influence others’ use. Participants also described thinking about when, where, and with whom they were going to use prior to doing so (e.g., only using in safe places and with people who they trusted). Finally, they described a range of consequences they experienced (e.g., getting sick, getting in trouble), and a subset of transgender participants described experiencing dependence symptoms. These findings suggest that substance use prevention and harm reduction interventions for bi+ male youth should address diverse motivations for use, including general stressors, which are often overlooked compared to minority-specific stressors. Further, interventions should approach youth as capable of making decisions. Findings also highlight the particular need to address substance use among transgender youth.