<p>In the last decades, the relationship between the gut microbiome and response to anticancer therapy has been extensively studied. Increasing evidence shows that gut microbes can influence both the therapeutic efficacy and toxicity of anticancer therapy through multiple mechanisms, including immune regulation, drug metabolism, and modulation of the tumor microenvironment. Unlike host genetics, the gut microbiome can be relatively easily modified by non-invasive interventions. While most microbiome-modulating strategies are still in the experimental phase and not yet widely applied, they offer the potential to optimize the efficacy and safety of anticancer therapies. Several microbiome-modulating strategies, including probiotics, postbiotics, antibiotics, dietary components, fecal microbiota transplantations (FMT) and bacterial specific inhibitors, have been explored in preclinical and clinical studies that provided initial evidence that gut microbiome modulation may enhance treatment efficacy and reduce toxicity. In this review, we summarize the current evidence on microbiome-based interventions aimed at improving anticancer therapy outcomes. We discuss the key results from preclinical and clinical interventions, and evaluate their safety and feasibility. We also address major limitations in current research and outline future directions to translate microbiome-modulating strategies into clinical practice. By providing an overview of these strategies, this review aims to support the development of personalized strategies to optimize anticancer therapy through targeted modulation of the gut microbiome.</p>