Advances in affordable genetic engineering have accelerated the creation and large-scale environmental release of genetically modified microorganisms (GMMs). While beneficial applications exist, GMMs may present unique, long-term risks to human and environmental health. Unlike static chemicals, GMMs are biologically active, self-replicating entities capable of rapid mutation and global dispersal. Current regulatory frameworks place responsibility on each country to regulate GMMs, without a clear, coordinated international policy. This review details critical risk scenarios, including horizontal gene transfer to native species and the possible disruption of vital human microbiomes (gut, oral, and infant), which could increase resistance to degradation, promote traits that expand a microbe’s range of hosts or ecological niches, and enhance the production of novel metabolites with unexpected biological activity. In soil, GMMs may support the emergence of “super bugs” or destabilize carbon sequestration cycles, potentially impacting climate resilience. Engineered microbial enzymes in the food supply may also act as environmental drivers of autoimmunity. Given the limited understanding of microbial ecology, we propose a decision-based biosafety workflow emphasizing pre-release risk assessment and continuous post-release monitoring. We urge national and international regulators to adopt the precautionary principle to better protect human health and the environment from the potential negative outcomes of GMMs.