Obesity and associated diseases such as diabetes have become an epidemic that represents a major threat to global public health. In the last two decades, an explosive increase in the number of persons diagnosed with diabetes has been observed worldwide. The global figure of affected individuals is expected to increase from currently 150 million to 300 million in 2025. The obesity spectrum diseases also impact individuals at a young age, posing a tremendous burden on the global public health system. Dietary interventions and pharmacological strategies have so far failed to deliver appreciable success in the fight against obesity. This paper examines the emerging role of metabonomic-based gut microbiome biomarkers for personalized interventions against obesity. We also highlight that chronobiology is a potentially relevant consideration for systems biology research in obesity. Mechanism-oriented molecular diagnostics for obesity offer the promise to substantively influence the long term trajectory of obesity related diseases and create a space whereby preventive public health interventions can be designed effectively. Human gut and microbiome warrant attention in future research efforts for personalized medicine, and rational therapeutics for obesity and the associated continuum of diseases.