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The gut microbiome is increasingly recognised as a clinically modifiable determinant of efficacy and toxicity across systemic cancer therapies, with the most mature evidence in patients receiving immune checkpoint inhibitors (ICIs). The composition and function of intestinal microbes can influence treatment outcomes by affecting immune priming, antigen presentation, host-microbial co-metabolism, drug biotransformation, and epithelial barrier integrity. In melanoma, non-small-cell lung cancer, and renal cell carcinoma, higher microbial diversity, ecological stability, and enrichment of immunostimulatory pathways have been associated with improved ICI response and survival. By contrast, antibiotics and proton pump inhibitors are linked to inferior outcomes because they disrupt the microbiome. Microbiome-directed interventions, including faecal microbiota transplantation, dietary modifications, prebiotics, probiotics, and live biotherapeutic products, are undergoing clinical testing but remain at the investigational stage. This Review synthesises current evidence linking the intestinal microbiome to anticancer therapy outcomes, evaluates strategies and challenges for therapeutic modulation of the microbiome, and introduces emerging insights into the mycobiome.