Despite decades of work, behavioral interventions for obesity are not yet able to facilitate long-term weight loss maintenance for most participants. The current manuscript proposes an acceptance-based, self-regulation framework for understanding the challenge of maintaining changes in weight-related behavior and describes how this framework can be integrated into the behavioral treatment of obesity. According to this framework, intrinsic drives to consume palatable, high-calorie food interact with a modern environment in which high calorie foods are easily accessible. This combination produces a chronic desire to eat unhealthy foods that exists in opposition to individuals’ weight control goals. Similarly, energy expenditure requirements in the modern environment are limited, and people’s innate preferences to conserve energy typically prevent the concerted effort that would be necessary to engage in lifestyle activity and structured activity. Both external (e.g., sight of food) and internal (e.g., an aversive emotion) cues motivate overeating and sedentary behavior. However, individuals vary in their responsivity to these cues. While standard behavior skills may enable those lower in responsivity to successfully achieve weight control, we suggest that those higher in responsivity need specialized self-regulatory skills to maintain healthy eating and exercise behaviors. These skills include an ability to tolerate uncomfortable internal reactions to triggers and a reduction of pleasure, behavioral commitment to clearly-defined values, and metacognitive awareness of decision-making processes. So-called “acceptance-based” interventions based on these skills have so far proven efficacious for weight control, especially for those who are the most susceptible to eating in response to internal and external cues (as predicted by the model). Despite the current empirical support for the postulated model and for the interventions which stem from it, much remains to be learned including whether acceptance-based interventions will prove efficacious in the longer-term.