Microbial-based therapies have emerged as a promising frontier in cancer treatment. Traditional therapies often lack specificity and cause harmful side effects, necessitating more targeted approaches. Microorganisms naturally exhibit tumor-targeting properties and complex interactions with the tumor microenvironment. They can exert direct antitumor effects or serve as delivery vehicles for therapeutic payloads. This comprehensive chapter explores the potential applications of microbes in cancer management under the One Health initiative framework. Bacteria demonstrate direct anticancer activities through secretion of cytotoxic elements and antiproliferative effects. Certain species preferentially colonize hypoxic tumor niches. Genetic engineering enables tumor-specific targeting and delivery of cytotoxic genes, prodrug-activating enzymes, and immunomodulators. Oncolytic viruses selectively replicate within and lyse cancer cells, releasing tumor antigens to stimulate antitumor immunity. Viruses are engineered for enhanced targeting, replication, and immune stimulation. Fungi and protozoa also show promise, with β-glucan modulating the tumor microenvironment. Probiotics and prebiotics impact cancer prevention, progression, and treatment response through modulation of inflammation and immunity. Microbial therapies face challenges including balancing virulence reduction without compromising antitumor effects. Achieving full tumor eradication requires attention to tumor heterogeneity and resistance mechanisms. Optimization of delivery methods is crucial to disseminate therapies systemically. Combination therapies integrating microbes with chemotherapy, radiation, or immunotherapy show enhanced efficacy and reduced toxicity. The One Health initiative recognizes the interconnectivity between human, animal, and environmental health factors impacting cancer risk. It emphasizes multidisciplinary collaboration to address challenges like antimicrobial resistance through prudent antimicrobial use. Continued advancements in genetic engineering, delivery methods, and characterization of combinatorial regimens hold the potential to further optimize microbial cancer treatments. Rigorous clinical evaluation is imperative. Microbial therapies represent a significant stride in cancer management by focusing on targeted delivery coupled with activation of innate and adaptive antitumor immunity. With ongoing developments, these innovative approaches offer hope for more effective and less toxic personalized therapies.