Human-associated microbes hold immense therapeutic potential, yet most species remain undomesticated due to cultivation barriers and limited genetic tools. Recent advances in genetic engineering are overcoming these challenges, enabling the precise manipulation of both domesticated and previously intractable microbes. This review highlights established strategies for engineering domesticated strains, such as Escherichia coli Nissle 1917 and lactic acid bacteria, for diverse therapeutic applications. We also discuss emerging tools, including optimized transformation protocols for skin commensals and genome-editing approaches for Clostridium species and undomesticated E. coli, that address key barriers in non-model microbes and expand the potential of engineered microbiome therapeutics.