The rapid advancements in synthetic biology have allowed for the development of revolutionary technologies such as bacteriophage-mediated gene and microbiome therapies. These technologies create the need for management of the upcoming risks and uncertainties. Safe-by-Design is a strategy to build in safety measures in an effort to mitigate and anticipate risks in synthetic biology applications. This study aims to portray a nuanced review of the opportunities and challenges posed by Safe-by-Design through a case study on this year’s iGEM project, the application of gene and microbiome therapy principles to mitigate the issue of Desert Locust swarms. To gather an all-round perspective on the current state of synthetic biology, bacteriophage-based therapies, and Safe-by-Design, these aspects are assessed in terms of governance. Synthetic biology regulations have long ensured safe research practices, but the lack of adequate regulations for novel phage-based technologies hampers the development of this field of research. In further detail is discussed how the use of the precautionary principle guarantees biosafety but also limits the discovery of risks and uncertainties. Downstream Safe-by-Design is proposed as a method to facilitate policy-making and to tackle concerning issues such as transnational regulations and public perception of biosafety. In this report, the risks associated with the application of bacteriophages for non-therapeutic purposes are determined and multiple Safe-by-Design approaches are analyzed to mitigate these risks and uncertainties. This resulted in the collection of quorum sensing, kill switches, encapsulation, anti-CRISPRs, and auxotrophy as suitable Safe-by-Design measures for this project. Furthermore, the challenges and limitations regarding the application of Safe-by-Design are reviewed. This analysis concludes that uncertainty and a lack of knowledge of the intricate synthetic biology systems are the main constrains on Safe-by-Design for synthetic biology. Lastly, it is concluded that Safe-by-Design is a promising strategy to ensure biosafety because of its dynamic and proactive character, and recommendations are made to stimulate future progress in this area of research.