Obesity has been considered a paradigm for many of the common chronic non communicable human diseases of the globalization, which generally result when multiple inherited susceptibility variants interact with the ‘Westernised’ environment to modulate disease predisposition. Recent large scale twin studies confirmed the important role of inherited factors in the development of obesity. Furthermore, a non negligible fraction of early onset severe obesity cases carry DNA defects in a single gene resulting in dramatically impaired appetite regulation. These (rather unexpected) discoveries have greatly improved our understanding of the role on the energy balance of the leptin-melanocortin pathway in humans. Recent analyses of the impact of MC4-R non synonymous missense mutations in large populations have shown that both lack and gain of function exist, leading to either severe obesity or a significant protection against overweight. However, even in this model the environment may modulate the obesity phenotype. Polygenic obesity genetics is still poorly understood but past and on-going genome wide studies bring new harvest of genes and loci that have been proven to increase the risk for obesity. In this regard, the recent discoveries of frequent DNA variants (SNPs) in the hypothalamus expressed Fat mass and Obesity associated FTO and Proconvertase 1 (PCSK1) genes and in the MC4-R regulatory region evidence that proteins involved in food intake behaviour regulation are indeed contributing to the development of obesity in humans. Apart from frequent SNPs, it is likely that many rare mutations, copy number variation and epigenetic factors in these genes and in others may participate to obesity pathophysiology. The emerging picture of obesity molecular mechanism includes different genetic mechanisms including allelic selection in the Neolithic age, the accumulation of pathogenic rare mutations, as well as the strong effect of recent obesegenic pressure on “thrifty genes”ancestral alleles. Elucidating genetic effects should not only bring novel and unsuspected hypotheses but will also support epidemiological studies in order to differentiate etiological and confounding factors. Will the human genome give us the answer to obesity? A debate – and the case against.