Synthetic biology combines biology and engineering to design and reprogram biological systems for new functions. It differs from the standard genetic engineering strategies of deletion and introduction of genes and proteins from one organism to another. Instead, the synthetic biology tools encompass the use of bioinformatics, biological systems, and genetic engineering strategies to accurately identify the causative agent and then modifying the biological system in a novel way. This offers immense potential for advancements in global health, environmental sustainability, and industrial biotechnology. The unprecedented progress of this field depends on a proactive, adaptive governance framework that incorporates “safety-by-design” principles, a culture of responsible innovation, and proactive management of risks. However, it also presents significant challenges in terms of biosafety, which necessitate addressing risks like unintended ecological consequences and ethical issues such as double-edged helix. This chapter explores the ever-changing challenges and risks associated with the synthetic biology strategies. It points out the shortcomings of the current risk assessment methods, especially when dealing with products of advanced gene editing tools such as CRISPR and gene drives. The chapter also discusses clear distinction between biosafety and biosecurity, terms that are often used interchangeably. It further delves into the ethical and social conundrums on how to handle dual use dilemmas, navigate through the misuse of advanced synthetic biology tools, equitable access, and to build public trust in science.