Childhood obesity is the result of a complex interaction of multiple behavioral, biological and environmental factors that impact long term energy balance. The prevalence of childhood obesity is increasing around the world at an unprecedented rate and changes in lifestyles have likely been a primary factor that has been most consistently associated with childhood obesity across many countries. However, lifestyle behaviors are complex and are affected by multiple levels of influence, including local and national policies, the physical or built environment, numerous behavioral settings and domains and intrapersonal characteristics. The primary aim of ISCOLE is to determine the relationship between lifestyle and weight gain and obesity in a large multi-national study of children and to investigate the influence of behavioral settings and physical, social and policy environments on the observed relationships within and between countries. The results of ISCOLE will provide new and important information that will help in the development of lifestyle interventions to address childhood obesity that can be culturally adapted for implementation around the world. Much of the information available on the role of personal lifestyle behaviors and the influence of multiple levels of influence as described in the Ecological Model of Four Domains of Active Living has come from studies conducted in North America and Europe. There is a pressing need to determine the robustness of the relationship between lifestyle traits and obesity across all global regions and to understand the influence of behavioral settings and the role of physical, social and policy environments on the interaction between lifestyle and obesity. These questions can only be answered with a multi-national study of lifestyle and obesity.