Commensal microbes inhabit barrier surfaces, providing a first line of defense against invading pathogens, aiding in metabolic function of the host, and playing a vital role in immune development and function. Several recent studies have demonstrated that commensal microbes influence systemic immune function and homeostasis. For patients with extramucosal cancers, or cancers occurring distal to barrier surfaces, the role of commensal microbes in influencing tumor progression is beginning to be appreciated. Extrinsic factors such as chronic inflammation, antibiotics, and chemotherapy dysregulate commensal homeostasis and drive tumor-promoting systemic inflammation through a variety of mechanisms, including disruption of barrier function and bacterial translocation, release of soluble inflammatory mediators, and systemic changes in metabolic output. Conversely, it has also been demonstrated that certain immune therapies, immunogenic chemotherapies, and checkpoint inhibitors rely on the commensal microbiota to facilitate anti-tumor immune responses. Thus, it is evident that the mechanisms associated with commensal microbe facilitation of both pro- and anti-tumor immune responses are context dependent and rely upon a variety of factors present within the tumor microenvironment and systemic periphery. The goal of this review is to highlight the various contexts during which commensal microbes orchestrate systemic immune function with a focus on describing possible scenarios where the loss of microbial homeostasis enhances tumor progression.