Engaging partners for tobacco control within low and middle income countries (LMICs) at early stages of tobacco control presents both challenges and opportunities in the global effort to avert the one billion premature tobacco caused deaths projected for this century. The Dominican Republic (DR) is one such early stage country. The current paper reports on lessons learned from 12 years of partnered United States (US)-DR tobacco cessation research conducted through two NIH trials (Proyecto Doble T, PDT1 and 2). The projects began with a grassroots approach of working with interested communities to develop and test interventions for cessation and secondhand smoke reduction that could benefit the communities, while concurrently building local capacity and providing resources, data, and models of implementation that could be used to ripple upward to expand partnerships and tobacco intervention efforts nationally. Lessons learned are discussed in four key areas: partnering for research, logistical issues in setting up the research project, disseminating and national networking, and mentoring. Effectively addressing the global tobacco epidemic will require sustained focus on supporting LMIC infrastructures for tobacco control, drawing on lessons learned across partnered trials such as those reported here, to provide feasible and innovative approaches for addressing this modifiable public health crisis.