Eating and physical activity behaviors associated with adult obesity have early antecedents, yet few studies have focused on obesity prevention interventions targeting very young children. Efforts to prevent obesity beginning at birth seem particularly important in populations at risk for early-onset obesity. National estimates indicate that American Indian (AI) children have higher rates of overweight and obesity than children of other races/ethnicities. The Prevention of Toddler Obesity and Teeth Health Study (PTOTS) is a community-partnered randomized controlled trial designed to prevent obesity beginning at birth in AI children. PTOTS was developed to test the effectiveness of a multi-component intervention designed to: promote breastfeeding, reduce sugar-sweetened beverage consumption, appropriately time the introduction of healthy solid foods, and counsel parents to reduce sedentary lifestyles in their children. A birth cohort of 577 children from five AI tribes is randomized by tribe to either the intervention (three tribes) or the comparison condition (two tribes). The strengths and weaknesses of PTOTS include a focus on a critical growth phase, placement in the community, and intervention at many levels, using a variety of approaches.