The gut microbiota is a complex and dynamic microbial ecosystem that plays a fundamental role in host physiology. Locally, the gut commensal microbes/host symbiotic relationship is vital for barrier fortification, nutrient absorption, resistance against intestinal pathogens, and the development and maintenance of the mucosal immune system. It is now clear that the effects of the indigenous intestinal flora extend beyond the gut, ranging from shaping systemic immune responses to metabolic and behavioral functions. However, the underlying mechanisms of the gut microbiota/systemic immune system interactions remain largely unknown. Myeloid cells respond to microbial signals, including those derived from commensals, and initiate innate and adaptive immune responses. In this review, we focus on the impact of the gut microbiota on myeloid cells at extraintestinal sites. In particular, we discuss how commensal-derived signals affect steady-state myelopoiesis and cellular function and how that influences the response to infection and cancer therapy.