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The gut microbiota has emerged as an important consideration in clinical oncology. The role of the microbiome in cancer extends beyond causation and cancer risk. It is now known that the microbiome not only acts at a local epithelial level in the gut but also modifies immune responses within intestinal and extraintestinal tumors. Microbial signaling influences the clinical course of cancer including the efficacy, bioavailability, and toxicity of chemotherapeutic and immunotherapy agents. This has focused research on microbiota profiling in different cancer states with an aim of developing prognostic biomarkers of risk. The potential value of microbiome manipulation with live biotherapeutics or microbial transplantation has also become a realistic consideration. Maintenance of microbial diversity in patients with cancer is a variable challenge given the modifying influences of the tumor itself, chemotherapy, nutritional status, and sporadic antimicrobial therapy. Here, we address current evidence for the role of the microbiome in cancer therapy.