Obesity is one of the greatest public health threats of the 21st century. Its prevalence has increased rapidly over the last few decades, particularly in developed countries. The importance of these observations relates to the comorbidities associated with obesity, including type 2 diabetes, cardiovascular disease and cancer. Lifestyle, environment and genetic factors are key drivers of the obesity epidemic. Many challenges exist in human obesity research. First, unlike animal studies, mechanistic based studies are limited in humans. Indeed, differences between animals and humans limit translatability between species. This is most classically exemplified by studies of molecules involved in the leptin-melanocortinergic pathway, which governs appetite regulation in animals and humans, albeit with some differences. Second, various phenotypic tools have been employed in clinical studies in obesity and metabolic disease. The quality of the outcomes of these studies is often proportional to the ‘deepness’ of the phenomic measures used. Tensions exist between studies of large numbers (e.g. in Genome Wide Association Studies) vs smaller phenomic studies of humans with monogenic obesity disorders. Third, it has not yet been established that personalised prevention and treatment of obesity will be successful. Detailed documentation of the underlying phenotype in obesity, with careful elucidation of substrate utilisation, fat distribution, muscle, liver and adipose tissue insulin sensitivity and circulating markers of insulin action and hormonal function, is essential in paving the way for individualised and more targeted treatment of obesity.