The human gut microbiota consists of about 3.8 × 10 microorganisms that play an essential role in health, metabolism, and immunomodulation. These gut microbes alter therapeutic response and toxicity to cancer therapies including cytotoxic chemotherapy, radiation therapy, kinase inhibitors, and immunotherapy agents. The gut microbiota generates short-chain fatty acids that are significant regulators of histone post-translational modifications that fundamentally regulate gene expression, linking the microbiota to cellular metabolism and transcriptional regulation. The short-chain fatty acids not only act locally but can be taken up in the blood stream to inhibit the activity of histone deacetylases, regulate gene expression in distant organs as well as the effector function of CD8+ T cells. Cancer and the treatments for it negatively impact the microbiome often resulting in dysbiosis. This can diminish a patient's response to treatment as well as increase systemic toxicities from these therapies. In addition to the gut microbiota, microbes have been detected in tumors that can modulate chemotherapeutic drug response and can result in immune suppression. The gut microbiota and tumor-associated bacteria may be a significant contributor to the interindividual differences and heterogeneous responses to cancer therapies and drug tolerability and strategies that support and/or manipulate the microbiota to improve therapeutic outcome is an emerging area for personalized cancer treatment.