Cancer is a globally challenging health problem threatening mankind. Despite therapeutic advances in dealing with this malignancy, heterogeneous response and resistance to chemotherapeutic agents remain the hallmarks of cancer therapy. On the other hand, the involvement of the microbiota in affecting human health is well defined. An ever-growing body of evidence implicates the potential link between the microbiome and the efficacy of cancer therapies. Gut microbiota can modulate the metabolism of drugs in a number of ways. The presence of bacteria within the tumor environment can also impact the responses to cancer therapies; changing the chemical structure of chemotherapeutic drugs, affecting their activity, and local concentration. However, the underlying mechanisms by which gut and tumor microbial communities affect the response to cancer therapy are poorly understood and deciphering these mechanisms is of paramount importance. This review provides an overview of how gut and tumor microbiota might affect the efficacy of chemotherapy, radiotherapy, and immunotherapy and alleviate the adverse side effects of these therapies for the development of personalized and effective anticancer therapy.