The obesity epidemic is spreading worldwide without reversal trend and despite specific policies oriented to dietary habits and lifestyle, which seem to have modest effects. Genetic factors only partly explain the rise, whereas environmental factors seem to play a key role, mainly by gene-environment interactions through epigenetic mechanisms. A number of animal and human studies point to maternal diet, intestinal microbiota and chemicals introduced as contaminants with food, all factors able to increase the risk of obesity. Widely diffused toxics (mainly BPA, phthalates, pesticides) are able to promote obesity in children and adults, mainly by acting on the differentiation pathway linking multipotent stromal stem cell to mature adipocyte, modulating epigenetic factors and influencing a series of mechanisms finally leading to altered dietary habits, increased adipocyte formation and fat storage. Furthermore, the adipose tissue is an important target for several chemicals (mainly POPs) which represent a threat to metabolic health. In conclusion, besides excessive individual energy intake and inadequate lifestyle, other broadly diffused and modifiable factors (mainly ingestion of toxic chemicals with food) seem to have a critical role in the rapid epidemiological growing of obesity, also considering trans-generational transmission of risk and later development of obesity due to exposure during early life. Further studies are needed, to better assess interactions between cumulative effects of toxic food contaminants and modification of diet and lifestyle, and to verify the efficacy of primary prevention strategies acting on all these factors and potentially able to reverse the continuous rising of the obesity epidemic.