The prevalence of obesity rose slowly in the first half of the 20th century, but between 1970-80 began to rise much more rapidly, and in many countries the prevalence of obesity (BMI > 30 kg/m2) now exceeds 30%. The genetic code in humans didn’t change during that time, but genetic variability which underlies the differential responses of people to the foods they eat and other environment factors may account for why some people become obese and others do not even when exposed to the same surplus of low cost, convenient and tasty foods. This could be stated as "genetic variability loads the gun – diet/environment pulls the trigger". This differential genetic response to environmental challenges provides the base for "natural selection" which may be seen in the rising risks of obesity for some people, but not others. A number of hypotheses have been proposed to explain the underlying physiological mechanism reflecting this genetic variability. The Protein Leverage hypothesis; The Increased Food Intake Hypothesis; The Hedonic Override Hypothesis; The Reduced Physical Activity Hypothesis; The Environmental Obesogen Hypothesis; The Stress from Income Disparity Hypothesis; The Microbiome/Inflammation Hypothesis; and The Refined Carbohydrate Hypothesis. These hypotheses will be discussed and an approach to prevention through "The Fluoride Hypothesis" will be presented.