Primary care practitioners (PCPs) have been encouraged to screen all adults for obesity and to offer behavioral weight loss counseling to the affected individuals. However, there is limited research and guidance on how to provide such intervention in primary care settings. This led the National Heart, Lung and Blood Institute in 2005 to issue a request for applications to investigate the management of obesity in routine clinical care. Three institutions were funded under a cooperative agreement to undertake the practice-based opportunities for weight reduction (POWER) trials. The present article reviews selected randomized controlled trials, published before the initiation of POWER, and then provides a detailed overview of the rationale, methods and results of the POWER trial conducted at the University of Pennsylvania (POWER-UP). POWER-UP's findings are briefly compared with those from the two other POWER trials, conducted at Johns Hopkins University and Harvard University/Washington University. The methods of delivering behavioral weight loss counseling differed markedly across the three trials, as captured by an algorithm presented in the article. Delivery methods ranged from having medical assistants and PCPs from the practices provide counseling to using a commercially available call center, coordinated with an interactive website. Evaluation of the efficacy of primary care-based weight loss interventions must be considered in light of costs, as discussed in relation to the recent treatment model proposed by the Centers for Medicare and Medicaid Services.