Highlights Models can investigate many more genome designs than laboratory research. Algorithms can search for genomes that optimise specific criteria. Together, models and algorithms can help engineers to design genomes. Algorithm-driven whole-cell modelin silicodesigns could be viableinvivo. The genome design ecosystem needs improved modelling and design tools. Abstract Large-scalein silicogenome designs are on the brink of being engineeredinvivo, offering a potential paradigm shift for cellular research (previous designs relied on fractured available knowledge andinvivoengineering iteration) by integrating computational design,in silicomodels and algorithms, with laboratory construction. However, several challenges remain. Ifinvivoengineering 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.