The commensal microbiome constitutes an important modulator of host physiology and risk of disease, including cancer development and progression. Lately, the microbiome has been suggested to modulate the efficacy of anti-cancer treatment. Examples include chemotherapy and total body irradiation-induced barrier function disruption, leading to microbial efflux that drives activation of anti-tumorigenic T cells; Microbiome-driven release of reactive oxygen species contributing to the efficacy of platinum salts; and microbiome-induced immune priming promoting the anti-tumor effects of alkylating chemotherapy and immune checkpoint inhibitors. Furthermore, selected commensals are able to colonize solid tumors. This 'tumor microbiome' may further impact local tumor responses to treatment and potentially be harnessed for tumor-specific targeting and therapeutic delivery. In this review, we present recent advances in understanding of the intricate role of microbiome in modulating efficacy of a number of anti-cancer treatments, and discuss how anti-cancer treatment approaches utilizing the tumor microbiome may enhance oncological treatment efficacy.