Thailand has joined other countries in developing biosafety guidelines that apply to all biotechnology research and development in the country and to the introduction of biotechnology products into the country. BIOTEC has been playing an important part in the formulation and management of biosafety regulations: introduction into the country, field testing, and monitoring. The recent emerging of the GMO issues with immediate crisis in socio-economic impacts has made the challenges increasingly complex and interdisciplinary, and at the same time it posed some question to the existing system. This paper describes what measures BIOTEC has been taking to ensure effective implementation of the regulations. It highlights the real-world challenges, some proposed strategies to address the challenges, and the lessons learned.