A systematic study on thermophilic anaerobic digestion of poultry waste was carried out at North Carolina State University over the last 35 years. The concept and experiments were initiated in the laboratory and technical feasibility was proven by a pilot-scale digester on the university farm and subsequently full-scale in China. Multiple benefits of the digester system in animal and crop productions, waste conversion, biogas production, nutrient recycle, farm sanitation and CO2 reduction were demonstrated. The possibility of financial gain was projected for an integrated system with an anaerobic digester at its core. Also, interestingly, a feather-degrading bacterium was isolated from the digester and, subsequently, a bacterial keratinase was purified. This enzyme was found useful in processing feather meal, degrading prion protein -which is the putative cause of bovine spongiform encephalopathy or commonly known as mad cow disease -and improving protein digestibility in animal feeds. As a feed enzyme, keratinase is now produced at industrial scale and marketed globally. A total of 12 patents were generated from this series of studies from waste management and energy production to enzyme technology. In the foreseeable future, new biotechnologies, including genomics, proteomics and bioinformatics, are able to probe into the complex bio-process for better understanding and improving biogas production. An integrated system, or Holistic Farming, is proposed to facilitate not only waste management and energy production, but also agricultural and environmental sustainability. This system could drive a new model of agriculture for the 21st Century.