The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency. With dozens of clinical trials underway, some researchers hold the following views: “humans are nearing the first commercial live bacteria therapeutic.” However, the facultative anaerobe Salmonella typhimurium VNP20009, which is particularly safe and shows anticancer effects in preclinical studies, had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects. This is almost certain to dis-appoint people's inflated expectations, but it is noted that recent state-of-the-art research has turned attention to bacteria-mediated synergisticcancer therapy (BMSCT). In this review, the foundation of bacteria-mediated bio-therapy is outlined. Then, we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities (chemotherapy, photothermal therapy, reactive oxygen and nitrogen species therapy, immunotherapy, or prodrug-activating therapy) in the past 5 years. Next, we discuss multiple administration routes of BMSCT, highlighting potentiated antitumor responses and avoidance of potential side effects. Finally, we envision the opportunities and challenges for BMSCT development, with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.