Long-haul truck drivers and members of their social networks in urban locales constitute a hard-to-reach population at risk for acquiring and disseminating STIs/HIV. This paper focuses on the unique logistical, methodological, and ethical challenges faced by population health scientists while studying long-haul truck drivers and members of their sexual networks in inner-city neighborhoods of a major US metropolitan center and the innovative strategies developed to overcome the challenges. Formative research and focus groups with several trucker-centered populations (N = 28) led to in-depth interviews and serologies with 60 truck drivers and 24 sexworkers. Various difficulties encountered by the research team are discussed, followed by strategies devised to overcome them.