Large-scale in-silico genome designs are on the brink of being engineered in-vivo, offering a potential paradigm shift for cellular research (previous designs relied on fractured available knowledge and in-vivo engineering iteration) by integrating computational design, in-silico models and algorithms, with laboratory construction. However, several challenges remain. If in-vivo engineering is successful, designing genomes can be used to gain new understanding of cellular life, improve the metabolite production process, and reduce the risk of unintended genetic modification and release. Here we review the progress so far. We suggest improvements on recent models and algorithms, illustrate the next steps for integrating computational and laboratory engineering, and offer our opinions on the future of the field.