Macrophages play a critical role in innate immunity. Differentiation Ags present on macrophages such as CD14 orchestrate the first line of defense against infection. The basal/homeostatic signaling scheme that keeps macrophages thus groomed for innate immune functions remains unresolved. Wnt5a-Fz5 signaling being a primordial event during cell differentiation, we examined the involvement of Wnt5a-Fz5 signaling in the maintenance of innate immune functions. In this study, we demonstrate that innate immune functions of macrophages ensue at least partly through a homeostatic Wnt5a-Fz5-NF-κB (p65) circuit, which is Rac1 dependent. The autocrine/paracrine Wnt5a-Fz5-Rac1-p65 signaling cascade not only maintains basal levels of the immune defense modulating IFNs and CD14; it also supports macrophage survival. Wnt5a-Fz5-Rac1 signaling mediated p65 homeostasis in turn sustains Wnt5a expression in a feed-forward mode. The natural immune response of macrophages to Escherichia coli/LPS and virus is accordingly sustained. The depiction of sustenance of innate immune functions as an outcome of a homeostatic Wnt5a-p65 axis unfolds previously unidentified details of immune regulation and provides new insight into homeostatic cell signaling.