Given the high prevalence of overweight and obesity worldwide and the fact that this trend shows no signs of slowing, it is urgent to take a new, multilevel approach to understanding the basis of the obesity epidemic and how to reverse it. In this Commentary paper, Huang and Glass explore four key areas: 1-cross-disciplinary hypotheses and questions, 2-policy interventions research, 3-capacity building in multilevel science, and 4-global perspectives. They conclude by reinforcing the notion that to succeed in the fight against obesity, strategies will have to be based on a fundamental understanding of the obesity epidemic, one that sees the epidemic as the result of a systemic alignment of factors at multiple levels of influence that interact to create what has become an obesogenic environment.