© 2018 Elsevier Inc. The debate on the relative contributions of presumptive etiologic factors in the development of obesity is becoming increasingly speculative, insular, and partisan. As the global prevalence of obesity continues to rise, the sheer volume of unfounded conjecture threatens to obscure well-established evidence. We posit that the failure to distinguish between causal factors and mere statistical associations engendered the proliferation of misleading and demonstrably false research programs and failed public health initiatives. Nevertheless, scientific progress necessitates the elimination of unsupported speculation via critical examinations of contrary evidence. Thus, the purpose of this review is to present a concise survey of potentially falsifying evidence for the major presumptive etiologic factors inclusive of ‘diet’ ‘genes’ physical activity, and non-physiologic factors from the social sciences. Herein, we advance two ‘Fundamental Questions of Obesity’ that provide a conceptually clear but challenging constraint on conjecture. First, why would an individual (i.e., human or non-human animal) habitually consume more calories than s/he expends? And second, why would the excess calories be stored predominantly as ‘fat’ rather than as lean tissue? We posit that the conceptual constraint presented by these questions in concert with the parallel trends in body-mass, adiposity, and metabolic diseases in both human and non-human mammals offer a unique opportunity to refute the oversimplification, causal reductionism, and unrestrained speculation that impede progress. We conclude this review with an attempt at consilience and present two novel paradigms, the ‘Metabolic Tipping Point’ and the ‘Maternal Resources Hypothesis’ that offer interdisciplinary explanatory narratives on the etiology of obesity and metabolic diseases across mammalian species.