Modern medicine has long studied the mechanism and impact of pathogenic microbes on human hosts, but has only recently shifted attention toward the complex and vital roles that commensal and probiotic microbes play in both health and dysbiosis. Fueled by an enhanced appreciation of the human−microbe holobiont, the past decade has yielded countless insights and established many new avenues of investigation in this area. In this review, we discuss advances, limitations, and emerging frontiers for microbes as agents of health maintenance, disease prevention, and cure. We highlight the flexibility of microbial therapeutics across disease states, with special consideration for the rational engineering of microbes toward precision medicine outcomes. As the field advances, we anticipate that tools of synthetic biology will be increasingly employed to engineer functional living therapeutics with the potential to address longstanding limitations of traditional drugs.